Peripherally-induced Movement Disorders: An Update

Hemifacial and Hemimasticatory spasm

HFS is probably the most common PIMD. Since the key mechanism of HFS is irritation of the facial nerve, a part of the peripheral nervous system, this movement disorder is regarded as a PIMD. It is characterized by involuntary, intermittent, irregular, tonic, or clonic contractions of muscles innervated by the ipsilateral facial nerve [19]. HFS is usually unilateral; there are rare reports of bilateral HFS [21, 22]. Although the majority of HFS are idiopathic, presumably due to irritation or compression of the facial nerve by an aberrant blood vessel in the middle or posterior fossa or other vascular condition (e.g., arteritis), there are other causes of facial nerve compression, including tumors [19, 23]. HFS may also be present in children; however, it is rare and is usually associated with vascular or tumor etiology [24, 25]. Especially common in people of Asian origin, HFS can also occur in families, although disease-specific gene mutation has not yet been identified [26, 27]. Neurologists should be familiar with other conditions that may mimic HFS. These include functional facial spasms, facial tics, facial dystonia, and facial myoclonus [19]. In a study from our center, lack of “other Babinski sign,” tonic muscle contractions, and downward deviation of angle of mouth had a high sensitivity for distinguishing organic HFS from functional (psychogenic) HFS [28]. The presence of additional focal neurologic or systemic signs should prompt a detailed workup to rule out secondary causes.

HMS may resemble HFS, but in contrast to facial nerve irritation or compression in HFS, the motor trigeminal nerve is affected in HMS [29]. Much less common than HFS, HMS is characterized by unilateral, involuntary, intermittent contractions of the jaw-closing muscles, resulting in brief twitches and/or spasms without actual jaw deviation [30, 31]. Patients with HMS may have additional features such as facial hemiatrophy, connective tissue disorders such as scleroderma, and skin changes such as morphea [32, 33, 34].

HFS and HMS usually markedly improve with botulinum toxin injection, especially when performed by experienced clinicians [35, 36, 37]. In addition, if there is a definite neurovascular compression, HFS and HMS may improve after surgical vascular decompression of facial or trigeminal nerve, respectively [38, 39].

Dystonia

Dystonia is one of the most commonly reported phenomenologies in patients with PIMD. In a systematic review, Van Rooijen and colleagues reported that the prevalence of dystonia among patients with PIMD was 72% [4]. Since fixed dystonia, a typical presentation of functional (psychogenic) dystonia, is more common than mobile dystonia after peripheral injury, some patients with peripherally-induced dystonia have been diagnosed with functional movement disorder [40, 41, 42]. Some key features of peripherally-induced dystonia include marked restriction of the range of movements, sometimes associated with contractures, lack of alleviating maneuvers (sensory tricks), frequent association with CRPS, and lack of a good response to botulinum toxin [2]. Pain is a common feature in patients with post-traumatic dystonia. Dystonia occurs in 20-30% of cases of CRPS, and in such cases, dystonia is usually fixed in nature [4, 13]. There is wide variability in the duration between the onset of CRPS and the emergence of dystonia in the first affected extremity (less than a week to up to a year). Compared to those without CRPS, patients with dystonia in the context of CRPS are usually younger and have a greater risk of the spread of dystonia in the future [4, 13]. One of the major risk factors for peripherally-induced limb dystonia is prolonged immobilization (termed “immobilization dystonia”), such as casting after a bone fracture. Okun and colleagues drew attention to this phenomenon in a series of four patients who developed dystonia after weeks of cast immobilization [43]. Only two of the four patients had associated pain, and none had CRPS. Thus while pain and CRPS are often associated with peripherally-induced dystonia, these elements are not always present [43].

Cervical dystonia (CD) has been commonly reported in the context of neck trauma and thus may be considered a form of peripherally-induced dystonia. In a series of 114 patients with CD, Sami et al. reported pre-existing head/neck injury (within one year of the onset of CD) in 12% of the patients. In that series, there were no striking clinical differences between patients with CD with and without pre-existing trauma [44]. Clinical features, however, may vary depending on the interval between trauma and the onset of dystonia. For example, patients with acute onset CD, compared to those with delayed-onset CD, have severely restricted cervical range of motion, more pain, higher incidence of shoulder elevation and laterocollis, lack of phasic involuntary movements, and poor response to botulinum toxin and physical therapy [45, 46, 47, 48]. Conversely, patients with delayed-onset CD are often clinically indistinguishable from those with idiopathic CD [49].

Other peripherally-induced focal dystonia include blepharospasm and oromandibular dystonia (OMD). A review of 264 patients with blepharospasm by Grandas and colleagues revealed the presence of pre-existing ocular lesions in 12.1% [50]. In addition, a strong association of ocular symptoms such as dry eyes with the occurrence of blepharospasm supports the concept of peripherally-induced blepharospasm [51]. While there are several publications on secondary blepharospasm in the context of central nervous system (CNS) lesions, peripherally-induced blepharospasm is relatively rare [52, 53].

OMD has been reported in individuals after face, mouth, or jaw injury or after dental surgical procedures [54, 55, 56]. The clinical phenomenology of post-traumatic OMD is often indistinguishable from primary OMD, which may pose diagnostic challenges [55]. The term “edentulous dyskinesia” describes new onset involuntary movements associated with dystonia after tooth extraction [57]. In a series of 14 patients with edentulous dyskinesia, dystonia was limited to the oral region and spared the tongue [58]. Compared to other forms of post-traumatic OMD, functional disability is usually minimal in patients with edentulous dyskinesia [57, 58]. It is essential to be familiar with edentulous dyskinesia as the symptoms may potentially improve with restoration procedures or fitting dentures [59]. The phenomenology of edentulous dyskinesia often overlaps with that of tardive dyskinesia [60]. It is, therefore, critical to explore the history of drug exposure, as dopamine receptor-blocking drugs (e.g., antipsychotics and antiemetics) are typically associated with tardive dyskinesia in the form of orofacial stereotypy or OMD [60]. Many other disorders should be considered in the differential diagnosis of OMD, including tics, bruxism, and others [54, 61].

As mentioned above, task-specific dystonia may also be considered a category of PIMD, particularly if occurring after prolonged repetitive motor activity (“overuse syndrome”) [8, 9]. Musicians and their physicians often attribute their task-specific dystonia to intense practice before an important performance, but the link with the overuse syndrome is often difficult to establish [10, 11]. While sports-related dystonia often follows some limb injury, the peripheral trigger may not always be obvious. Common forms of sports-related dystonia include golfer’s dystonia (often referred to as “yips”) and “runner’s dystonia.” However, many other sports activities can be associated with task-specific dystonia, including gymnastics, ice skating, tennis, table tennis, pistol shooting, petanque, billiards, and baseball [62]. While botulinum toxin injection by an expert often alleviates task-specific dystonia, many professional athletes and musicians have their careers threatened because of persistent movement disorder.

There is a huge unmet need for long-term outcome data on patients with peripherally-induced dystonia. In general, complete or meaningful recovery is highly unusual in patients with peripherally-induced dystonia, especially those with fixed dystonia and contractures. Some patients with post-traumatic CD, OMD, blepharospasm, or task-specific dystonias may respond well to local botulinum toxin injections [35]. However, co-existing functional (psychogenic) components or overlay may complicate the clinical course [18, 40, 63]. When co-existing functional component is suspected, patients should be referred for treatment (not diagnosis) to experienced psychologists and psychiatrists.

A few centers have used deep brain stimulation (DBS) or ablative lesions in the thalamus in treating post-traumatic and task-specific dystonia [64, 65]. Results have been disappointing in the former and encouraging in the latter [66, 67, 68, 69]. However, reports on these surgical interventions in PIMD are limited in number and methods of assessment.

Table 2 highlights the key differences between peripherally-induced dystonia and idiopathic dystonia.

Tremor

Post-traumatic tremor is the most common movement disorder caused by brain injury [70, 71], but peripherally-induced tremor is relatively uncommon. In one of the earliest reports of peripherally-induced tremors, five of 23 patients with PIMD had tremor; in one, tremor followed initial dystonia [72]. All had a unilateral hand or foot tremor except one patient with an electric shock injury who developed a bilateral hand tremor. In another series of 28 patients with dystonia and tremor after peripheral trauma, 17 had only tremor (mostly postural), and 11 had co-existing parkinsonism [16]. A family history of essential tremor was considered one of the common predisposing factors, although other genetic or environmental factors were proposed in this and other series of PIMD. There are reports of emergence of tremor after iatrogenic peripheral nerve injury (e.g., after thoracic surgery) [73] and traumatic neck injury [74]. The latter case is interesting because it provides insight into the neurophysiologic basis of peripherally induced tremor. The authors explored the effect of ischemic nerve block and torque loading on postural upper extremity tremor in a patient with a traumatic neck injury [74]. The outcome was a decrease in tremor frequency after both interventions, probably because tremor was secondary to abnormal peripheral mechanical reflex mechanisms [75].

Neuropathic tremor may be considered a form of PIMD. This form of tremor is present in some patients with severe peripheral neuropathy without other movement disorders [12]. Specific forms of peripheral neuropathy have a greater predilection for tremors than others. Patients with IgM paraproteinemic neuropathies, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy with conduction block, and Charcot-Marie-Tooth (CMT) disease are especially prone to experience tremor [76, 77, 78]. Although the mechanisms are not well understood and probably vary from case to case, the prevalence of tremor in inflammatory neuropathies may range from 40-70% [76, 78]. In a recent study of 24 patients with CIDP, 66% had an ET-like postural tremor [79]. Contrary to the presumption that tremor in neuropathy is primarily peripherally generated, the authors provide evidence for a co-existing role of a central component by demonstrating that tremor in CIDP was unaffected by weight loading [79]. Specific subtypes of CIDP, such as those associated with neurofascin155 (nfasc155) IgG4 antibodies, are particularly likely to be associated with disabling low-frequency, high-amplitude action tremor of the upper extremities [80, 81].

A newly described genetic disorder named “myogenic tremor,” first reported in 2019, may be considered a form of peripherally-induced tremor [82, 83]. This genetic disorder, transmitted by an autosomal dominant pattern, results from a mutation in the MYBPC1 gene (codes for myosin binding protein). MYBPC1 mutation affects the binding of MBPC1 to myosin, resulting in dysregulated cross-bridge cycling during sarcomeric contraction. In addition to proximal myopathy and skeletal deformities (scoliosis, thoracic deformities), all patients in the published study had postural hand tremor [83]. Patients with this condition have tremor from the neonatal period that persists until adulthood. One patient described in the first original publication on myogenic tremor had tongue tremor since neonatal life. The investigators speculate that the myogenic tremor has a sarcomeric origin which gets support from the fact that MYBPC1 is expressed only in the skeletal muscles, and the mutation is primarily linked to dysregulated cross-bridge cycling during sarcomeric contraction [83]. The jerky component of the tremor suggests a possible link to polyminimyoclonus (discussed below). Recent neurophysiologic studies suggest that while the tremor may originate within muscles, it may engage muscle spindles to activate central mechanisms and tremor oscillators [84].

Parkinsonism

Whether peripheral trauma precipitates parkinsonism or worsens pre-existing parkinsonism has remained controversial since the first description of Parkinson’s disease (PD) by James Parkinson [85]. Repeated head trauma and even single traumatic brain injury have been proposed as risk factors for parkinsonism [86, 87, 88, 89], but the data on peripheral trauma triggering parkinsonism is relatively sparse. Earlier reports from our center described well-documented cases of parkinsonism developing a few days or weeks after peripheral trauma [16]. The lack of improvement with dopaminergic drugs suggests the possibility of a post-synaptic component. Many patients with PD report injury, such as motor vehicle accidents, prior to the onset of their symptoms. Such history is often dismissed because of possible recall bias and the presumption that the patients were simply unaware of any parkinsonian manifestations before the trauma. There are, however, many reports of musculoskeletal problems, especially “frozen shoulder,” before the onset of classic parkinsonian symptoms that are often attributed to local injury. While it can be argued that those are early symptoms of PD (such as decreased arm swing leading to a “frozen shoulder”), shoulder pain is now well recognized early symptom of PD [90, 91, 92, 93, 94]. Although the relationship between shoulder problems and PD is not well understood, we and others have encountered many well-documented cases of parkinsonism with onset within days or weeks following shoulder injury [16].

In one intriguing study from the Mayo Clinic, 10 out of 44 (23%) patients diagnosed with CBS had a history of limb immobilization or trauma in the most affected limb [20]. In six patients, immobilization/trauma preceded the onset of CBS symptoms, whereas four patients had pre-existing limb dysfunction that significantly worsened after immobilization/trauma. While more extensive studies are required to understand this association better, this study highlights the potential association between peripheral trauma and CBS [20]. This association is particularly intriguing because CBS is the most asymmetric of all neurodegenerative parkinsonian disorders [95]. In our clinical practice (unpublished data), we have encountered several patients who developed CBS a few days or weeks after peripheral trauma or surgery (with apraxia or dystonia on the ipsilateral side).

Myoclonus and polyminimyoclonus

In the systematic review by van Rooijen et al. that reviewed 713 patients (from 133 publications), 95 patients (13%) had myoclonus, in isolation or combination with other movement disorders, after peripheral trauma [4]. There are reports of different types of myoclonus (segmental, propriospinal) after accidental and iatrogenic injuries [96, 97, 98]. Myoclonus may coexist with dystonia and tremor in some patients with CRPS [13]. Several case reports have described myoclonus emerging after peripheral nerve injury [96, 99, 100, 101, 102, 103, 104]. One of the most vital pieces of evidence in favor of the concept of “peripherally-induced myoclonus” is that in many patients with peripherally-induced myoclonus, nerve block with local anesthetics ameliorates the myoclonus [102, 103]. It is presumed that peripheral nerve or root injury, in some individuals, triggers ephaptic transmission and ectopic excitation that could be associated with the emergence of myoclonus. This is especially relevant in cases of spinal segmental myoclonus, manifested by rhythmic, jerk-like contractions of muscles (or other dyskinesias, such as rotatory movement of the scapula or “belly dancer” dyskinesia) innervated by cervical, thoracic or lumbar roots. Such segmental movements have been described after peripheral or spinal injury, procedure, or surgery [105, 106, 107]. Treatment of spinal myoclonus with tetrabenazine was first described by Hoehn and Cherington [108]. We have also found the use of vesicular monoamine transporter 2 inhibitors, in addition to clonazepam, helpful in treating spinal myoclonus. Patients with bothersome peripherally-induced myoclonus may benefit from local botulinum toxin injections, which result in chemodenervation of the intrafusal muscle fibers and, in turn, reduces the spindle afferent input [96, 100].

Polyminimyoclonus (also called minipolymyoclonus) is a type of involuntary hyperkinetic movement that is often described in patients with anterior horn cell diseases such as amyotrophic lateral sclerosis and brachial monomelic amyotrophy (Hirayama disease) [109]. It is characterized by intermittent, slow, small-amplitude movements of hands, especially of the digits. In a series of 77 patients with various motor neuron diseases, more than two-thirds of patients had involuntary movements of their hands [110]. Polyminimyoclonus was documented at rest and during action in 39.2% and 32.8%, respectively. Other involuntary movements were thumb tremor and pseudo-dystonic posturing of the thumb [110]. Most patients with Hirayama disease, who are typically adolescent males with initially progressive hand weakness and atrophy, also have polyminimyoclonus [111, 112]. Although the precise neuroanatomical correlates are poorly understood, it is speculated that polyminimyoclonus is probably a result of frequent fasciculations, which give the appearance of myoclonic movements [111]. That is why some have proposed the term “polyminifasciculations” [109, 113].

Miscellaneous peripherally-induced movement disorders

A plethora of PIMD, other than those mentioned above, have been reported in the past, and we briefly describe those below.

Motor tics have been reported after peripheral injury [114, 115, 116]. These tics usually occur in adults but are phenomenologically similar to the childhood-onset tics associated with Tourette syndrome, even associated with a sensory urge prior to the movement.

Although rotatory movements of the scapula and other abnormal involuntary movements of the shoulder are typical manifestations of dystonic tics in patients with Tourette syndrome, shoulder involuntary movements may be peripherally induced. One cause of shoulder (scapular) dyskinesia is neuralgic amyotrophy [117]. This condition, manifested by episodes of acute pain in the proximal arm, presumably due to acute autoimmune inflammation of the nerves in the brachial plexus, is often associated with abnormal involuntary movements of the shoulder. Dancing dorsal quadrilaterals is a recently described syndrome manifested by repetitive, rotatory movements of the scapular region, especially the trapezius and rhomboids, occurring after spine instrumentation [118]. Another movement disorder involving the shoulder includes “scapular dyskinesis,” presumably secondary to the instability of the shoulder joint or abnormalities in the pectoralis muscle following shoulder surgery [119].

Pseudoathetosis may be considered a form of PIMD. The term “athetosis,” which has a Greek origin meaning “without a fixed position,” refers to an involuntary movement characterized by slow, writhing movements (essentially slow chorea). Although typically encountered in patients with basal ganglia lesions, athetosis may also occur in the setting of profound loss of proprioception, hence the term pseudoathetosis [120]. Since phenomenologically, it is identical to athetosis of central origin, a more appropriate term should be “proprioceptive athetosis.” Typically involving the fingers or toes, in contrast to central athetosis, the proprioceptive athetosis (pseudoathetosis) usually worsens when the eyes are closed [121]. There are many etiologies of pseudoathetosis, but it is typically caused by large fiber peripheral neuropathy [121, 122, 123]. Proprioception abnormalities secondary to CNS lesions, such as parietal cortex stroke [124], neuromyelitis optica [125], or cervical myelopathy [126] may also cause pseudoathetosis.

PLMT is a rare PIMD where limb pain is a key feature. In a series of 76 cases, 42% were cryptogenic, whereas in other cases, the common etiologies were peripheral neuropathy, trauma, and radiculopathy [127]. PLMT may have unilateral or bilateral leg involvement, and the onset of pain almost invariably precedes the onset of involuntary movements. While there are reports of improvement in symptoms by medications such as pregabalin [128], gabapentin [129], and clonazepam [130], the overall response to treatment is not satisfactory in the majority of cases, but local botulinum toxin injections may be beneficial [127, 131]. Corresponding symptom complex in the upper extremities has been reported as “painful arm moving finger” syndrome [132]. Very rarely, patients with PLMT may have involuntary movements in the ipsilateral hand [133]. A phenomenologically similar condition, but without pain, is described as “painless leg moving toe” syndrome, which has been reported in several conditions such as multiple system atrophy [134], Wilson’s disease [135], and Parkinson’s disease [136].

Some patients may develop a variety of movement disorders after surgery, even if the surgery is not directly related to the nervous system. Some of the examples include dystonic gait after hip surgery [137], hemi-abdominal myoclonus after uterine surgery [138], dyskinesia along scar tissue which was named “scar dancing syndrome” [139], and post-amputation stump dystonia and dyskinesia [140, 141]. We refer the readers to a recently published review that describes post-surgical movement disorders in detail [142].

Figure 1 summarizes the phenomenology of PIMD.