Tremor in Pediatric Populations: Clinical Characteristics, Differential Diagnosis, and Management Challenges

Abstract

Background

Tremor is a hyperkinetic movement disorder defined as a rhythmic, involuntary, oscillatory movement of a body part. It can present as early as in the neonatal period and may be an isolated finding or part of an associated neurological or systemic disorder. Although it is commonly seen in childhood, it is not frequently described in the literature.

Objectives

This review aims to provide a clinically useful overview of pediatric tremors based on the current literature.

Methods

We identified relevant studies published in English by searching PubMed (until February 2024), using the following subject headings: pediatric/tremor, deep brain stimulation, and focused ultrasound.

Results

Data from 65 articles were critically reviewed with focus on tremor classification, etiologies, clinical features, and management.

Conclusion

Some tremor disorders in children can persist into adulthood, however, others are exclusively seen in the pediatric population. The lack of epidemiological and clinical studies in the pediatric population creates substantial challenges for pediatricians, and medical decisions are mostly guided by adult data.

The Taskforce on Childhood Movement Disorders ¹ defines tremor as a rhythmic, relatively symmetric, back‐and‐forth, or oscillating involuntary movement about a joint axis. Tremors are usually of central origin and linked to the presence of oscillators within the cortico‐lenticular‐thalamic‐cortical and the cortico‐cerebellar‐thalamic pathways. Peripherally mediated processes may be implicated as well. ² Tremor is less frequent in the pediatric population compared to adults, however, many tremor syndromes can present throughout childhood, including the neonatal period. ³ Causes for tremor (Table 1) can range from benign conditions including enhanced physiological tremor to more serious diseases.

TABLE 1.

Tremor etiologies

Idiopathic

Neonatal tremor (present <3 days)

Shuddering attacks

Jitteriness

Enhanced physiological tremor

Spasmus nutans (can be associated with intracranial pathology)

Essential tremor

Geniospasm (can be hereditary)

Acquired and inherited

Medications (see Table 5) and drugs

Toxins and heavy metals

Metabolic/endocrine Thyroid disorders Hypoglycemia Hypocalcaemia, hypomagnesaemia, hyponatremia Vitamin B12, D deficiency

Genetic and degenerative conditions (see main text for more details) Wilson's disease Infantile and juvenile parkinsonism Dopa responsive dystonia syndromes Mitochondrial diseases Ataxia telangiectasia Phenylketonuria Galactosemia

Structural etiologies and trauma Locations: cerebellum, brainstem, thalamus – Tumor – Metastases – Hemorrhagic or ischemic infarction – Vascular malformations – Abscess – Tuberculoma 3rd ventricle cyst Hydrocephalus Functional/psychogenic

Examining pediatric patients can be challenging as it relies on patient cooperation and often, the pediatrician is restricted to merely patient observation. This may impede the correct classification of tremor phenomenology or the differentiation from other movement disorders. Moreover, electrophysiological studies such as surface electromyography are less established or not available in the pediatric setting. As such, the neurological assessment can be time consuming and may require the use of toys, iPads, or the implementation of games.

The lack of epidemiological studies and therapeutic clinical trials in the pediatric population creates substantial challenges for physicians and often medical decisions are guided by adult data. ² The goal of this review is to provide a clinically useful overview of pediatric tremors discussing tremor classification, different tremor presentations based on age and available therapies.

Methods

Search Strategy

A comprehensive PubMed search was designed and conducted by the authors for articles published until February 2024. The search keywords included “pediatric tremor” OR “pediatric AND tremor” OR “pediatric AND tremor” AND “deep brain stimulation” OR “pediatric AND tremor” AND “Focused ultrasound” and was constrained to articles published in English. Additional constraints included human studies and publications limited to 18 years of age. The search strategy resulted in a total of 695 records. Initial search results were screened for relevance, and full‐text articles from the resultant list were evaluated for inclusion. No article type was excluded, and there were no limitations to inherent study design. We subsequently reviewed the articles' references to identify suitable publications not populated by the keywords‐based search string. A total of 65 articles were included in this review, comprising seven reviews and 58 original articles.

Results

Figure S1 provides decision tree‐type organizational diagram of the material covered in the review. Treatment recommendations derive mainly from adult data unless indicated otherwise.

Tremor Classification

Tremor can be classified in many ways ⁵ including anatomical location, etiology, frequency, and according to the circumstances under which it occurs. Rest tremor occurs when a body part is supported against gravity and the muscles are not activated. A rest tremor decreases or disappears with action, whereas it becomes more pronounced with agitation or distraction. Once the tremor subsides on taking up a new position rest tremors may re‐emerge after variable periods if the limb is held in the new position.

Action tremor occurs during any voluntary movement and can be further divided into a postural, kinetic, and isometric tremor. A postural tremor can be observed when a limb is maintained in a position against gravity such as extending the arms. Typically, there is little or no latency between taking on the new position and the development of a postural tremor, in contrast to a re‐emergent resting tremor. Kinetic tremor is subdivided into simple kinetic (during simple movements of a limb) in which the tremor remains grossly unchanged throughout a movement versus an intention tremor, in which there is an increase in tremor as the affected body part approaches a target.

Other forms of an action tremor are a position‐specific postural tremor, which occurs when a specific position or posture is maintained, and a task specific kinetic tremor, which presents during a specific task such as writing.

Isometric tremor occurs during a muscle contraction against a stationary object, such as holding an object or when making a fist. ⁵

Tremors can be further characterized by their amplitude (eg, large, intermediate, or small) and frequency. Tremor frequency is often categorized as low (<4 Hz), moderate (4–8 Hz), and high (>12 Hz), whereas the frequency of most pathological tremors is between 4 and 8 Hz. ⁵ , ⁶ To precisely and most accurately characterize tremor frequency, the use of a motion transducer or electromyography ⁵ is recommended.

Last, tremor can be further classified by age of onset, for example: infancy (birth to 2 years), childhood (3–12 years), adolescence (13–20 years), early adulthood (21–45 years), middle adulthood (46–60 years), and late adulthood (>60 years). ⁵

Previously, the etiological classification of pediatric tremor has been separated into primary (or idiopathic) when no cause could be identified, and secondary (or symptomatic) when there was an identifiable cause for the tremor. ⁷ In 2018, the Task Force of the International Parkinson and Movement Disorder Society proposed a two‐axis approach ⁵ similar to the earlier dystonia classification and consensus statement. ⁸ Axis I describes the clinical characteristics of tremor and axis II addresses tremor etiology, divided into three main groups: inherited (genetic), acquired, and idiopathic. Figure 1 summarizes our approach to axis I, adopting an update to the dystonia classification in progress (Albanese et al, personal communication). In “isolated” tremor, tremor is the only motor feature with an otherwise benign neurological examination. In “combined” tremor, the tremor is combined with other movement disorders, neurological, and/or systemic manifestations.

FIG. 1.

Tremor classification based on clinical characteristics. Several components can change with time, so patients need to be assessed and features documented prospectively in evaluating the clinical axis.

Tremor in Neonates

Terminology and Phenomenology

The classification of neonatal tremors is more ambiguous compared to tremor classification in children and adults, as often other terms including shudders, shivers, or jitteriness are used. These terminologies appear to be used interchangeably with tremors and are defined variably depending on the author. ⁹ Previously, shuddering has been described as brief episodes of shivering‐like movements of the head, shoulders, and arms. ¹⁰ Jitteriness is described as involuntary, rhythmic tremors of equal amplitude around a fixed axis ¹¹ decreased by passive limb flexion, in the absence of abnormal eye movements or autonomic signs. ¹²

Neonatal tremor is characteristically, a high frequency and low amplitude tremor involving the mandible and becomes more apparent during distress such as crying. ¹³ It may be variable in location, involving multiple locations or the whole body. ¹⁴ , ¹⁵ , ¹⁶ Neonatal tremors have been reported in association with specific risk factors ¹¹ , ¹² , ¹⁷ (Table 2). Physiologic tremors can be confirmed in the absence of hypoglycemia and when the neonate demonstrates a positive response to the suckling stimulation test. During this test, the neonate is placed supine with head straight and both hands free. When the examiner places their finger in the neonate's mouth, the tremors halt and return on removal of the examiner's finger. A pathologic tremor persists despite sucking or other soothing activities in a non‐crying neonate. ¹⁸

TABLE 2.

Neonatal tremor risk factors (adapted from Armentrout and Caple ¹² )

Maternal risk factors

Maternal substance abuse Prenatal teratogenic exposure Maternal diabetes Maternal thyrotoxicosis Maternal infection Maternal bleeding Signs of placental insufficiency

Perinatal risk factors

Fetal distress Use of anesthesia Difficulty of delivery Resuscitation provided Perinatal asphyxia

Postnatal or fetal risk factors

Low birth weight/prematurity Intrauterine growth retardation Hypoxic–ischemic insult Periventricular‐intraventricular hemorrhage Congenital central nervous system malformations Neonatal drug withdrawal Hypothermia Sepsis/meningitis Congenital infection Metabolic complications: Hypoglycemia Hypocalcaemia Hypomagnesemia Hyponatremia Hypernatremia Vitamin D deficiency 9

Congenital Tremor

In recent years, variants in several genes have been identified to present with congenital tremor as well as a variety of other manifestations. These include pathogenic variants in MYBPC1, which present with early and predominant myogenic tremor followed by gradual progressive myopathy. ¹⁹ , ²⁰ , ²¹ , ²² , ²³ Of note, the term “myogenic tremor” has only recently been acknowledged as a novel tremor entity. Unlike most pathological tremors, its pacemaker is thought to be located in the sarcomeric myofilaments ²⁴ (ie, peripheral origin), linked to mutations in genes encoding sarcomere‐associated proteins. ²⁰ , ²² , ²⁵ It is typically of high frequency and low amplitude and can present as postural and intention tremor as well as jaw, lip, and lingual tremor.

Most recently, a novel de novo gain‐of‐function variant of the CACNA1D gene has been identified with prenatal‐onset of severe tremor and other abnormalities such as developmental delay and seizures. ²⁶ Last, a novel SCN4A variant has been linked to “congenital essential tremor” in a Kurdish family. ²⁷ Please see Supporting Information for links to congenital tremor videos.

Benign Neonatal Tremor

This is the most common movement disorder seen in neonates and young infants, ¹¹ observed in 44% of healthy term neonates. ²⁸ Neonatal tremors (often referred to as “jitteriness” in the literature) in otherwise healthy newborns, are principally considered to be benign, and usually disappear by the third day of life. ²⁹ Leone et al ³⁰ observed that neonatal tremors can have a variable evolution and rate of resolution, with 70% recovery by 9 months with a normal outcome at 24 months in all low risk term neonates. Their results are in agreement with previous reports ¹⁵ , ²⁹ , ³¹ and a recent retrospective study. ¹⁶

Pathological Neonatal Tremor

There are tremor syndromes that are specific to neonates including neonatal hyperexcitability syndrome, characterized by a coarse tremor in mildly asphyxiated neonates with increased reflexes and excessive Moro response. ³²

Generally, neonates who have fine tremors (high frequency, low amplitude) while quiet or asleep or whose tremors initially present beyond the third day of life require some laboratory work up dependent on the clinical situation (Table 3). Persisting and all coarse tremors (low frequency, high amplitude) are more likely to be associated with a pathology such as an intracranial abnormality ¹² , ³² and warrant a more comprehensive evaluation ²⁹ , ³³ (Table 3). Further investigations should be based on the individual clinical presentation, medical and perinatal history, or neonates appearing generally unwell, which includes unstable vital signs, lethargy, and decreased oral intake and output. ³²

TABLE 3.

Evaluation for neonatal tremor ^a (modified from Armentrout and Caple ¹² )

Metabolic workup: Complete blood count Electrolytes and extended lytes Serum glucose Liver function tests Thyroid studies Kidney function tests Vitamin D, B12 level

Blood gases

Urine drug screen

Serum cortisol level

Septic work up: Complete blood cell count Blood cultures Cerebrospinal fluid analysis and cultures Urinalysis and culture

Serum rapid plasmin reagin titers and urine cytomegalovirus culture

Serum amino acids and urine organic acids

Ceruloplasmin

Electroencephalogram

Neuroimaging

Genetic testing

^a Based on individual clinical presentation.

The prognosis for neonates with tremor generally depends on the underlying etiology and the degree to which it can be reversed. ¹²

Tremor in Infancy

Shuddering are brief episodes (<20 seconds) of high frequency tremor resembling shivering, without the loss of consciousness. These episodes are commonly associated with head and trunk flexion, accompanied by stiffness of the extremities. ³⁴ , ³⁵ Shuddering attacks begin in infancy or early childhood with up to 100 episodes per day. ³⁴ The etiology is unknown and prognosis is excellent as nearly all resolve by age 7, requiring no specific therapy. ³⁶ Some ³⁷ have linked shuddering to essential tremor (ET), but this relationship remains controversial. ³⁶

Spasmus nutans is characterized by the triad of head tremor, head tilt, and nystagmus. ³⁸ , ³⁹ The head tremor is of a variable frequency (usually 2–4 Hz) and direction. It usually appears in the first year of life. Most cases are idiopathic, however, cranial imaging is warranted as intracranial lesions have been associated with this syndrome. ⁴⁰ , ⁴¹ , ⁴² , ⁴³ Spontaneous recovery occurs within few months in most idiopathic cases, ⁴⁴ but symptoms occasionally persist for up to 2 to 3 years. ⁴⁵

Head nodding is comparatively slow and low frequency (about 2 Hz) in a “yes‐yes” direction seen during infancy, often initially noticed in the first few months of life as head control is attained. Head nodding can be pathologic in the context of weakness and the inability maintaining the head in a stable position, or it can be a compensatory phenomenon in the presence of congenital nystagmus. ⁴⁶ , ⁴⁷ , ⁴⁸

Bobble‐head doll syndrome is characterized by head movement, usually in a “yes‐yes” direction, with a higher frequency and lower amplitude than head nodding and can be intermittent and even suppressed by distraction and voluntary movement of the limbs. It has been associated with intracranial abnormalities such as tumors or cysts within the region of the third ventricle and hydrocephalus. ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ It may resolve if there is an effective treatment of the underlying etiology. ⁵⁴ , ⁵⁶ , ⁵⁷

Infantile tremor syndrome is almost exclusively reported in the Indian subcontinent ⁵⁸ , ⁵⁹ because of vitamin B12 deficiency in infants being breast‐fed by strict vegetarian mothers. Clinical features are variable, but include a combination of tremor and myoclonus, particularly involving the face, tongue, and pharynx. ⁶⁰ Infants may demonstrate depigmentation of hair, developmental regression, anemia, and hypotonia. This tremor responds to vitamin B12 supplementation, ⁶¹ but developmental delays are common. ⁶²

Please see Supporting Information for links to different tremor phenomenologies in neonates and infants.

Tremors in Childhood and Adolescence

Tremor accounts for approximately 10% to 20% of pediatric movement disorders. ⁶³ The prevalence of mild tremor in 819 examined school age children in Spain was at 51.7%, ⁶⁴ and more common in males. Similarly, mild tremor in either hand was seen in 105 (33.1%) of a total of 317 examined children in New York City. ⁶⁵ Tremors occurring before age 5 to 7 are often concerning for static or metabolic encephalopathies (see Table 1, Tables S1 and S2), whereas tremors that start during adolescence are more frequently related to enhanced physiologic tremor, functional tremor, substance‐induced, and ET. ⁶⁶ , ⁶⁷

ET

The International Parkinson and Movement Disorders Society, ⁵ defines ET as an isolated tremor syndrome of bilateral upper limb postural or kinetic tremor, with or without head tremor or tremor in other locations, with at least a 3‐years history of tremor and no neurological cause found. ET is generally reported to be the most common tremor in children between the ages of 4 to 17, followed by enhanced physiologic tremor, ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹ although published data regarding ET in the pediatric population is limited. ⁶⁶ ET is also the most common movement disorder in adults, ⁷² and tremor onset is commonly reported in childhood. ⁷³ , ⁷⁴ , ⁷⁵ , ⁷⁶

ET is often familial, ⁷⁷ however, the genetics of ET remain elusive and only a few loci have been identified so far. ⁷⁸ , ⁷⁹ , ⁸⁰ , ⁸¹ , ⁸² The mean age of childhood onset ET is approximately 6 years, ⁸³ and it follows a bimodal curve, with a peak in late childhood and approximately age 60. ⁸⁴ , ⁸⁵ Yet, some authors ⁶⁹ , ⁸⁶ have reported earlier symptom onset, including neonatal presentations. ⁷⁰

The typical clinical presentation of ET is the gradual onset (over years) of a postural tremor involving both upper extremities, although asymmetry can be present ⁸⁷ (see Supporting Information for video link). Other areas affected include head/neck, face, tongue, voice, ⁷⁴ , ⁷⁵ , ⁸⁸ , ⁸⁹ , ⁹⁰ and less frequently the lower extremities. ¹³

ET frequency ranges between 4 and 12 Hz. In the pediatric population, the mean frequency is approximately 7 Hz. ⁹¹ Additional myoclonic jerks may be more common in children ⁹² compared to adults with ET. ⁷⁴

ET frequency is inversely proportional to the tremor amplitude, and over time the frequency gradually becomes slower and the tremor becomes more pronounced leading to functional impairment and psychological distress. ⁹² ET also often spreads to other body regions. ⁶⁶ ET is generally to be a monosymptomatic disorder, ⁹³ , ⁹⁴ however, other comorbid features such as mild dystonia and parkinsonism (“ET plus”) are now acknowledged. ⁹⁵ , ⁹⁶ , ⁹⁷

The list of differential diagnoses of ET in childhood is short, particularly when consensus criteria are met. The most important conditions that should be excluded are hyperthyroidism and Wilson's disease (WD) (see later in text) because these require disease specific treatment. ⁶⁶

Treatment of ET (Table 4) in the pediatric population is reserved for those with functional and/or social limitations, which applies to approximately 25% of patients. ⁹⁸ This is usually less common in childhood, but may increase in adolescence. There are no evidence‐based guidelines for the treatment of ET in children and data derives mainly from the adult population (Table 4). Past case series ⁸³ , ⁹⁶ , ⁹⁹ report a benefit with first line medications such as propranolol in approximately half of patients and 22% with primidone. ⁹⁶ Second line medications include gabapentin, topiramate, and benzodiazepines, reported to be effective in approximately 25% to 35% of adult populations. ¹⁰⁰ , ¹⁰¹

TABLE 4.

Medications used in essential tremor (modified from Uddin and Rodnitzky ¹³ ).

Medication	Dosage	Side effects
Propranolol	0.5–1 mg/kg to 4 mg/kg/day divided by 2 to 3 doses a	Fatigue, hypotension, depressive feelings; CI: heart failure, bradyarrhythmias, reactive airway disease
Primidone	<8 years: 10–25 mg daily up to 250 mg per day >8 years: 100–125 mg daily up to 375 divided by 3 doses b	Sedation, nausea, ataxia, confusion
Gabapentin	20–30 mg/kg/day to 50 mg/kg/day divided by 3 doses Dose limit: 3600 mg/day b	Dizziness, fatigue, headache
Topiramate	1–3 mg/kg/day divided to 2 doses to 5–9 mg/kg/day divided to 2 doses. Dose limit: 400 mg/day c	Renal stones, drowsiness, psychomotor slowing, cognitive impairment
Benzodiazepines (eg, clonazepam*)	* ≤10 years or ≤30 kg: 0.01–0.03 mg/kg/day to 0.1–0.2 mg/kg/day divided by 3 doses * ≥10 years or ≥30 kg: 1.5 mg/day to 20 mg/day divided by 3 doses d	Sedation, drowsiness, drug dependence

^a See Ferrara and Jankovic. ⁶⁶

^b Pediatric and neonatal Lexi‐drugs.

^c Zesiewicz et al. ¹⁰²

^d Medscape.

Abbreviation: CI, contraindicated.

Botulinum toxin A may be beneficial for medically refractory head and voice tremors, which are less responsive to oral agents, ⁶⁶ however, chemodenervation has not been studied in pediatric patients despite its use in other movement disorders. ¹⁰³ , ¹⁰⁴

Last, deep brain stimulation (DBS) ¹⁰⁵ and stereotactic ablation ¹⁰⁶ , ¹⁰⁷ , ¹⁰⁸ targeting the ventral intermediate nucleus of the thalamus has been deemed safe and effective for adults with ET. The safety of DBS in children is unknown, as lead (electrode) migration because of body growth is of concern in children beyond the age of 5 years. ⁶⁶ DBS has been used off‐label in pediatric patients with post‐traumatic tremor ¹⁰⁹ and other movement disorders. ¹¹⁰

Parkinsonian Tremor

In contrast to adult‐onset idiopathic Parkinson's disease (PD), resting tremor in childhood parkinsonism is rare and should alert the physician to the possibility of a neurodegenerative form of juvenile parkinsonism. Juvenile‐onset Parkinson syndromes may manifest both rest as well as postural and action tremors. “Juvenile Parkinson's disease” (JPD) is most often secondary to biallelic mutations in the PRKN gene. Other autosomal recessive causes of JPD include mutations in PINK1 and DJ‐1.

The frequency of PRKN mutations in patients with early onset PD varies between 35% and 77% (0–20 years), 17% to 26% (21–30 years), and 2% to 3% (31–40 years) based on two multicenter studies. ¹¹¹ , ¹¹² Nonetheless, the median age at onset is 31 years (range, 3–81 years) with juvenile onset (< 21 years) in only 19%. ¹¹³ The median age at onset of a PINK1 mutation is 32 years (range, 9–67 years) with juvenile onset in 15% and a DJ‐1 mutation 27 years (range, 17–40 years) with juvenile onset in 13%. ¹¹⁴

Management of JPD includes the use of levodopa, anticholinergics, dopamine agonists, and inhibitors of dopamine catabolism. Patients with JPD endorse more commonly motor fluctuations and medication‐induced dyskinesias (this is an important differentiation between the excellent levodopa response in these patients and that of the parkinsonian presentation of some patients with the most common form of dopa‐responsive dystonia because of heterozygous mutations in the GCH1 gene). Carbidopa/levodopa dose should be initiated at 1 mg/kg/day (of levodopa) and can be increased up to 20 mg/kg/day. ²

There are many other possible causes for childhood‐onset parkinsonism including structural, ¹¹⁵ , ¹¹⁶ infectious, ¹¹⁷ and numerous neurodegenerative and neurometabolic diseases (eg, Huntington's disease (HD), Rett syndrome, pantothenate kinase‐associated neurodegeneration, Niemann‐Pick type C, WD, and dopa‐responsive dystonias). ⁷

Last, drug‐induced parkinsonism, secondary to dopamine receptor blocking agents or dopamine depleting drugs, should be always excluded. ²

Dystonic Tremor

Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal movements, postures, or both. ⁸ Dystonic movements may be tremulous (dystonic tremor) and dystonia may be associated with a tremor similar to ET (“dystonia with tremor”). Tremor prevalence in isolated and combined dystonia ranges from 14% to 86.67%. ¹¹⁸ A recent review investigated the prevalence and clinical characteristics of tremor in different types of primary monogenic dystonia. ¹¹⁹ Autosomal recessive DYT‐HPCA was found to have the highest prevalence of tremor among all the defined genetic dystonias where tremor onset can be in childhood, adolescence, or early adulthood. ¹²⁰ , ¹²¹ Other genetic dystonias ¹¹⁹ associated with tremor during childhood include DYT‐ANO3, DYT‐THAP1, DYT‐PRKRA, DYT‐TOR1A, DYT‐KMT2B, and DYT‐GNAL. ¹²² Among the combined dystonias, DYT‐SLC6A3 was most frequently associated with tremor. Tremor has also been reported in myoclonus‐dystonia in two defined genetic disorders, DYT‐KCTD17 and DYT‐SGCE. ¹¹⁹

Limb tremor has been reported in a child with a TUBB4A mutation, ¹²³ and there are reports of 18p deletion syndrome with adult onset tremor. ¹²⁴ , ¹²⁵

Dystonic tremor occurs in a body part affected by dystonia and its differentiation from other tremors is critical, as the evaluation and treatment differ considerably (Video 1). Onset during infancy can be associated with metabolic disorders such as tyrosine hydroxylase deficiency with two of its variants being treatable with levodopa (dopa‐responsive dystonia and infantile parkinsonism). ¹²⁶ Dopa‐responsive dystonia is most often caused by mutations in the GCH1 gene and typically presents between 2 and 6 years of age, although later presentations are common. ¹²⁶ Other conditions that may present with dystonic tremor in children includes galactosemia, glutaric acidemia type I, pantothenate kinase‐associated neurodegeneration, and dystonic cerebral palsy. ²

VIDEO 1.

A 9‐year‐old female with dystonic tremor after an episode of acute necrotizing encephalopathy of childhood.

Children with dystonia require brain imaging and a trial of levodopa should be attempted in every patient with dystonia or parkinsonism. Other therapies include anticholinergics, benzodiazepines, baclofen, chemodenervation, and DBS. ²

Importantly, dystonia in children may be the initial manifestation of WD because of biallelic mutations in the ATP7B gene that codes for a copper‐transporting ATPase. ¹³ Tremors in WD may be rest, postural, or kinetic or a combination of all. ¹³ The classically described upper limb “wing beating” tremor, because of its proximal component, ¹²⁷ is probably less common in WD than highlighted in the literature. Isolated tongue tremor has also been described. ¹²⁸

Cerebellar Tremor

A cerebellar tremor is an intention tremor that displays a larger amplitude as the body part is approaching a target and can be accompanied by other cerebellar features such as dysarthria, nystagmus, and ataxia (see Supporting Information file for link to video). Cerebellar tremors are usually of lower frequency (typically ~3 Hz). The numerous primary (eg, ataxia telangiectasia) and secondary (eg, structural lesion, infectious, and drugs) etiologies presenting with cerebellar tremor are beyond the scope of this review. It may be difficult to differentiate severe ataxia (where the movement is more irregular and less clearly rhythmic) from cerebellar tremor, and electrophysiological assessment can be very helpful in this regard. ¹²⁹ , ¹³⁰

Complex Tremor Syndromes

The previous sections dealt with conditions where tremor is the dominant or main movement disorder. A variety of metabolic and neurometabolic disorders can be associated with tremor, but not as the sole neurological manifestation. Examples include phenylketonuria, ¹³¹ pyruvate carboxylase deficiency, ¹³² galactosemia, ¹³³ glut‐1 deficiency, ¹³⁴ and homocystinuria. ¹³⁵ A coarse tremor has been reported in children with a tetrahydrobiopterin (BH4) synthesis defect, which leads to elevated phenylalanine levels. The treatment includes a low‐phenylalanine diet, supplementary BH4, and a neurotransmitter precursor, such as 5‐hydroxytryptophan or levodopa. ¹³⁶ , ¹³⁷

Mitochondrial encephalopathies, including Leigh syndrome (with many genetic causes), can occasionally cause tremor, but is more commonly associated with dystonia and rigidity. ¹³⁸

Tremor as a component of other movement disorders such as dystonia, ataxia, parkinsonism, and chorea has been described in numerous conditions and is beyond the scope of this review. To mention a few, ataxia telangiectasia may present with action, intention (Video 2) or dystonic tremors. ² Ataxia with vitamin E deficiency (AVED), or familial isolated vitamin E deficiency, is a rare autosomal recessive neurodegenerative disease because of mutations in the gene for α‐tocopherol transfer protein (α‐TTP). Patients present with their first neurological symptoms between 4 and 18 years of age, which include limb and gait ataxia, dystonia, head titubation, and head tremor (often considered a dystonic head tremor). ¹³⁹ , ¹⁴⁰ Early therapy with vitamin E has shown to stabilize and improve the neurological signs. ¹³⁹ , ¹⁴¹ Juvenile HD may present with rest, postural, and action tremors. In contrast to adult‐onset HD, children show a preponderance of parkinsonism and rigidity (ie, the Westphal variant). ¹⁴² , ¹⁴³

VIDEO 2.

A young female with a diagnosis of ataxia telangiectasia with appendicular ataxia and intention tremor worse on the right‐side during finger to nose testing.

Other genetic conditions in which tremor has been reported include spinal muscular atrophy, ¹⁴⁴ 18q syndrome, ¹⁴⁵ juvenile Canavan disease, ¹⁴⁶ 9p13 deletion syndrome, ¹⁴⁷ Rett syndrome, ¹⁴⁸ 48,XXYY syndrome, ¹⁴⁹ 47,XYY and 47,XXY syndrome, ¹⁵⁰ hereditary spastic paraplegia‐15, ¹⁵¹ SPG9B, ¹⁵² and channelopathies with pathogenic variants in the KCNN2 gene. ¹⁵³

Oro‐Palatal Lingual Tremor

Essential palatal tremor (EPT) is described as rhythmic palatal movements secondary to the activation of the tensor veli palatini muscle (Video 3). A cardinal symptom of EPT is the presence of ear clicks that are typically absent in symptomatic palatal tremor (SPT), ¹⁵⁴ which results from a lesion within the connections of the dentate nucleus of the cerebellum and the inferior olivary complex (also known as the Guillain‐Mollaret triangle), a phenomenology exclusively seen in the adult population. ¹⁵⁴ , ¹⁵⁵ EPT is not associated with a focal brain lesion and the pathophysiology remains elusive. ¹⁵⁵ Based on previous reports, etiologies of EPT are variable including a central generator, peripheral/mechanical, voluntary/special skill similar to ear wiggling or voluntary opening and closing of the eustachian tube in context of an upper respiratory tract disturbance and a “psychogenic” or functional origin. ¹⁵⁶ , ¹⁵⁷ , ¹⁵⁸ A total of 70% or more of patients with EPT are found to have psychogenic/functional palatal origin. ¹⁵⁹ Clinically, functional palatal tremor is entrainable and distractible such as during jaw closure and opening and performing various tasks with the hands (eg, finger tapping at different frequencies), however, volitional control is generally denied by the patient. ¹⁵⁸ Failure to assess patients for these positive signs lead to delay in diagnosis, unnecessary diagnostic testing, and inappropriate treatment. ¹⁵⁸

VIDEO 3.

A young girl with essential palatal tremor and audible click. Note, the suppression of the movements and entrainment of tremor frequency during finger tapping.

EPT typically presents at 6 and 9 years of age and symptoms can persist for months or years, but often disappear spontaneously between 3 months and 5 years after onset. ¹⁶⁰ , ¹⁶¹ The symptoms in children can fluctuate and often diminish during sleep. However, EPT, especially the ear clicks, can be debilitating to some with limited treatment options available. Medications that have shown some response include: anticonvulsants, ¹⁶² , ¹⁶³ , ¹⁶⁴ sumatriptan, ¹⁶⁵ , ¹⁶⁶ flunarizine, ¹⁶⁷ tetrabenazine, clonazepam, and botulinum toxin. ¹⁶⁸ , ¹⁶⁹ , ¹⁷⁰ , ¹⁷¹ , ¹⁷² , ¹⁷³ , ¹⁷⁴ , ¹⁷⁵ With the increasing recognition that a large proportion of EPT is functional in origin, there is a strong possibility that many of the benefits claimed with these treatments relate to a placebo response.

Of note, epileptic palatal myoclonus or epilepsia partialis continua with palatal tremor has been observed, but this entity also involves twitching of perioral muscles and twitching of the floor of the mouth. ¹⁷⁶ , ¹⁷⁷ Other conditions that have been associated with SPT or lingual tremor include juvenile‐onset Alexander disease, ¹⁷⁸ and patients with MYBPC1 variants ²³ who display an undulating, myogenic tongue tremor.

Geniospasm

Geniospasm is a paroxysmal movement disorder of the mentalis muscle resulting in trembling of the chin ¹⁷⁹ (Video 4). It is a rare autosomal dominant condition, but can also occur sporadically. ¹⁸⁰ , ¹⁸¹ One locus for hereditary geniospasm has been linked to the proximal long arm of chromosome 9q13‐q21, ¹⁸² but others have not, indicating genetic heterogeneity. Typically, stress or strong emotions can trigger the trembling movements of the chin, but it can also occur spontaneously. ¹⁸³ There might be a response to alcohol consumption. ¹⁸⁴ The typical age of onset is in infancy or early childhood and episodes may reduce with age. ¹⁸⁵ The severity of symptoms can vary and it has been associated with nocturnal tongue biting, ¹⁸⁶ , ¹⁸⁷ , ¹⁸⁸ and with social anxiety and embarrassment. ¹⁸⁹ Local botulinum toxin injection into the mentalis muscles is the most beneficial treatment approach with relatively no side effects and good tolerance. ¹⁹⁰ , ¹⁹¹ Effective doses of onabotulinum toxin A range from 5 to 30 units to each mentalis muscle. ¹⁹¹ Medications such as dopamine receptor blocking agents, anticonvulsants, benzodiazepines, beta‐blockers, and antihistamines showed inconclusive findings. ¹⁸⁵

VIDEO 4.

A young boy with hereditary chin tremor.

Acquired Tremor Etiologies

Drug‐Induced Tremor

Many drugs accentuate physiological tremor or cause tremor as a side effect ¹⁹² (Table 5) (Video 5). A parkinsonian rest tremor is usually seen in agents that modify dopaminergic neurotransmission such as neuroleptics. A postural or action tremor is usually seen with certain anticonvulsants and medications used in reactive airway disease. ¹³

TABLE 5.

Commonly used agents that can cause tremor (modified from Keller and Dure ⁴ )

Neuroleptics

Anticonvulsants Valproic acid Phenytoin Gabapentin Tiagabine Carbamazepine Lamotrigine

Lithium

Tricyclic antidepressants

Bronchodilators

Corticosteroids

Cyclosporine

Tacrolimus

Amiodarone

Serotonin reuptake inhibitors

Thyroid hormones

Amphetamines

Antihistamines

Caffeine

Alcohol (withdrawal)

VIDEO 5.

An 8‐year‐old girl with T‐cell acute lymphoblastic leukemia presenting with tremor in context of acute methotrexate toxicity.

Valproic acid (VPA) is known to cause tremor in 15% of patients. ¹⁹³ Patients with a family history of tremor have a higher risk of developing VPA‐induced tremors indicating an important effect of genetic background in the risk of VPA‐induced tremor. ¹⁹⁴ , ¹⁹⁵ Anticonvulsant‐induced tremor (VPA and others) is usually not a significant contributor to disability, however, rarely it does require cessation of the medication.

Although once considered solely a problem of the adult population, alcoholism and the use of psychoactive drugs as well as inhalant abuse such as toluene, propane, or acetone are on the rise in adolescent and preadolescent age groups. ¹⁹⁶ , ¹⁹⁷ , ¹⁹⁸ The possibility of alcohol withdrawal should be considered when a hospitalized adolescent develops unexplained postural tremor of the upper limbs and other body parts. ¹⁹⁹ , ²⁰⁰

Last, heavy metal intoxications such as mercury poisoning ²⁰¹ can also cause a postural and action tremor along with generalized parkinsonism. Intoxication with diethyltoluamide, commonly found in insect repellants ²⁰² may also cause tremor.

Post‐Traumatic Tremor

Different types of tremors can occur after head injury, most commonly observed between 3 and 18 months after injury. Predictive factors for the development of tremor include severity of trauma, loss of consciousness, coma, residual neurologic deficits, and generalized brain edema or focal lesions on initial brain imaging. ²⁰³ The occurrence of intention tremor after severe head trauma has been attributed to the damage to dentate‐rubro‐thalamic pathways in the midbrain. ²⁰⁴ Holmes' tremor, (previously called midbrain or rubral tremor) because of a lesion in the brainstem, cerebellum, or thalamus, manifests a combination of rest, postural, and intention tremors, usually of a low frequency (<4.5 Hz) and large amplitude. ²⁰⁵ , ²⁰⁶

Treatment options for post‐traumatic tremor include levodopa, beta‐blockers, or clonazepam with varying response. ²⁰⁷ , ²⁰⁸ Surgical options for treatment‐refractory or very disabling tremor include stereotactic thalamotomy or ventral intermediate nucleus DBS. ²⁰⁹ , ²¹⁰

Functional (Psychogenic) Tremor

Functional movement disorders (FMD), a heterogeneous group of motor disturbances, can be diagnostically and therapeutically challenging. ²¹¹ Tremor is the most common manifestations of FMD and mixed phenotypes are often seen. Ferrara and Jankovic ²¹² identified 54 patients with childhood‐onset FMD between 1988 and 2008, representing 3.1% of their pediatric movement disorder population and 5.7% of all FMD cases. Two‐thirds of their cases exhibited multiple FMD phenotypes, the most frequent being tremor followed by dystonia and myoclonus. Schwingenschuh et al, ²¹¹ found that dystonia was the most common FMD phenotype in children, followed by tremor and gait disorders.

FMD is more common in females, ²¹¹ , ²¹² and adolescent females appear to be at highest risk to develop FMD. ²¹² , ²¹³ , ²¹⁴ , ²¹⁵ The mean age of onset is approximately age 14, ²¹² and only a small portion presents before age 10, with age 7 being the youngest. ²¹¹ , ²¹² Often an underlying psychiatric diagnosis is present, the most common being conversion disorder followed by somatization disorder. Less commonly FMD is because of a factitious disorder (deliberate fabrication of symptoms for psychological gain) and rarely malingering (deliberate fabrication of symptoms for external/material gain). ²¹¹ Other comorbidities include anxiety, depression, and an “organic” neurological condition. In contrast to adults, ²¹⁶ , ²¹⁷ an underlying organic movement disorder is rarely reported. ²¹¹

Risk factors for FMD include a history of sexual abuse, previous surgery, physical trauma or preceding minor injury, and major emotionally stressful life events. ²¹⁸ , ²¹⁹ , ²²⁰

Typical features on history of a functional tremor include sudden onset, resolution, and recurrence (ie, periods of remission) and refractoriness to medications (although “organic” tremors may also be treatment resistant). Tremor phenomenology is characterized by unusual distribution of limb involvement, and unusual combinations of rest and action tremors, ²²¹ variability (of rate, amplitude, muscles involved and direction), distractibility (tremor changes amplitude or stops while being distracted) and entrainability (tremor assumes the frequency of other volitional movements) ² (Videos 6, 7, 8). Functional tremor most frequently involves the arms (when it is typically synchronous in the two arms in contrast to “organic” tremors), followed by the head and the lower limbs. ²²² In contrast to other FMD, functional tremor is usually diagnosed on purely clinical grounds and does not require extensive investigations. ²¹¹ In uncertain or challenging cases, electrophysiology studies can provide unequivocal support for the diagnosis. ²²³ , ²²⁴ , ²²⁵ Generally, functional tremor tends to have a more favorable prognosis compared to other pediatric functional movement disorders. ²¹¹ In the pediatric population, remission rates of patients with conversion disorder are between 85% and 97% ²²⁶ with lower rates in adults with only 10% to 36%. ²¹⁷ , ²¹⁸ , ²²⁰ Acute onset, short symptom duration (<1 month) or removal of a psychological stressor are best predictors of remission. ²²⁶ Patient and family education are important initial components of treatment, but some children may require psychiatric consultation for treatment of comorbid anxiety and depression. ²²⁷ Other treatment options include physical therapy, cognitive behavioral therapy, motor re‐training, and habit reversal therapy. ²²⁸ Most recently, a tremor retrainer smartphone application has been developed that could be potentially used as a widely accessible treatment option for older children with functional tremor. ²²⁹

VIDEO 6.

A teenager with functional tremor showing intermittent entrainment of tremor frequency and brief episodes of tremor suspension during alternate finger tapping.

VIDEO 7.

A female teenager with functional tremor displaying unusual distribution of limb involvement with variability of tremor rate, amplitude and muscle involvement.

VIDEO 8.

A young girl with functional tremor displaying unusual distribution of limb involvement and distractibility during alternate hand tapping and finger to nose testing.

Conclusion

Although pediatric tremor is common, it is infrequently and often inadequately described in the literature. Some tremor disorders are exclusively seen in the pediatric population, and others persist into adulthood. Tremor can present in isolation or as part of an associated neurological or systemic disorder. Causes range from benign conditions to more serious diseases, the presence of additional clinical features serving as an important clue to the latter. Importantly, treatable “not to miss diagnoses” include thyroid disorders, vitamin deficiencies, electrolyte disturbances, WD, dopa‐responsive dystonia, infantile and juvenile parkinsonism, medications, and drug abuse. The lack of therapeutic clinical trials in the pediatric population creates substantial challenges and medical decisions are mostly guided by adult data.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

C.M.G.: 1A, 1B, 1C, 3A

C.G.: 1A, 3B

A.E.L.: 1A, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. The authors confirm that ethical guidelines were followed to assure patient privacy was maintained. Written consent from patients or patient guardians were obtained before obtaining photo/video for purposes of education within a medical peer reviewed journal. The authors confirm to have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: C.M.G. declares that there are no additional disclosures to report. C.G. declares that she received honorarium and consulting fees from Medtronic and honorarium from Ipsen. A.E.L. has served as an advisor for AbbVie, Amylyx, Aprinoia, Biogen, BioAdvance, Biohaven, BioVie, BlueRock, BMS, Denali, Janssen, Lilly, Pharma 2B, Sun Pharma, and UCB; received honoraria from Sun Pharma, AbbVie and Sunovion; received grants from Canadian Institutes of Health Research, Edmond J Safra Philanthropic Foundation, the Krembil Brain Institute, The Michael J. Fox Foundation, Parkinson Foundation, Parkinson Canada, and The Rossy Foundation; is serving as an expert witness in litigation related to paraquat and PD, received publishing royalties from Elsevier, Saunders, Wiley‐Blackwell, Johns Hopkins Press, and Cambridge University Press.

Supporting information

Figure S1. Decision tree‐type organizational diagram of the material covered in the review.

Data S1. supporting Information.

Table S1. Secondary causes for parkinsonism.

Table S2: Neurodevelopmental disorders in which tremor has been reported.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.