Tremor is a rhythmic, involuntary back-and-forth oscillation of part of the body. It is described clinically by the location where it develops (hands, feet, back, neck, face, and voice), and the situations, postures, or movements that trigger or enhance it (action, at rest, and maintenance of a posture), and electrophysiologically by the frequency, amplitude, and pattern of muscle activation, as assessed by accelerometry and surface electromyography.

1. Rest tremor. Tremor that occurs in a body part that is not voluntarily activated and is completely supported against gravity. Rest tremor amplitude always diminishes during target-directed movements, which helps to separate rest tremor from postural tremors that continue when the limb is supported. It increases with mental stress (counting backwards), or when movements of another body part are performed (especially walking). It is mostly found in Parkinson’s disease (PD), but also in other parkinsonian syndromes, including drug-induced parkinsonism. Its presence indicates dysfunction of the nigrostriatal dopamine pathway or its efferent projections to basal ganglia-thalamo-cortical circuits.

2. Action tremor. Any tremor that is produced by voluntary contraction of muscle, and it includes postural, simple kinetic, intention tremor, and task-specific kinetic tremor.

1. Physiologic and enhanced physiologic.

2. Hereditary (familial, fragile X-associated tremor/ataxia syndrome [FXTAS], Wilson’s disease, spinocerebellar ataxias [SCAs], hereditary hemochromatosis, and acute intermittent porphyria).

3. Nonhereditary primary tremor: essential and orthostatic.

4. Degenerative: PD and other parkinsonisms.

5. Ischemic and posthypoxic.

6. Demyelinating disease.

7. Inflammatory, infectious or immunologic: AIDS and brain abscesses.

8. Neuropathic.

9. Endocrinologic/metabolic: thyroid and hypoglycemia.

10. Post-traumatic.

11. Drug-induced or toxic: valproate acid, amlodipine, selective serotonin reuptake inhibitors (SSRIs), prednisone, cyclosporine A, and tacrolimus (also see tardive syndromes).

Tremor is not associated with any uniform brain lesion or clear histopathologic changes in the brain. However, two regions within the central motor pathways, the inferior olive and the relay nuclei of the thalamus, demonstrate oscillatory behavior, and their pharmacologic manipulation in the harmaline mouse model may produce or improve tremor. These regions are functionally interconnected with the cerebellum. Thus, the inferior olive, relay nuclei of the thalamus, and the cerebellum are the principal candidates for the origin of any pathologic central tremor.

1. Physiologic tremor is a low-amplitude and high-frequency (8 to 12 Hz) postural tremor that is most prominent in outstretched hands. It can be present in normal subjects but can be enhanced under certain circumstances, including fever, drugs, excited mental states, alcohol withdrawal, and caffeine use.

2. Essential tremor is the most frequent neurologic disease causing tremor in the general population. It is an action tremor, mainly postural and kinetic. It is bilateral, largely symmetric, but it can be also asymmetric or even unilateral. The frequency usually is 4 to 12 Hz but may decrease with age. Conversely, amplitude increases during the
follow-up. Its major clinical feature is postural tremor of the hands, but it also can be present in other body parts (distal legs, voice, and head). About 5% of patients may present with tremor almost exclusively in the head and voice. Improvement of tremor amplitude with alcohol is a characteristic feature of the disease but is not present for most patients.

Although most patients have strong family histories, and three gene loci (ETM1 on 3q13, ETM2 on 2p24.1, and a locus on 6p23) have been identified in patients and families with the disorder, the cause of essential tremor is unclear. In recent years, systematic postmortem studies have shown essential tremor to be associated with clearly identifiable structural changes, including Purkinje’s cell loss, development of torpedoes in the cerebellum and, in some patients, deposition of Lewy’s bodies in the brainstem.

3. PD is the most frequent cause of rest tremor. It is typically defined by bradykinesia, rigidity, and impairment of postural reflexes. The neural correlates of rest tremor in PD are unknown, and the participation of other neurotransmitter systems apart from the dopaminergic dysfunction is likely. Parkinsonian tremor occurs at 3 to 7 Hz. It may be unilateral in the early stages of the disease, but it soon spreads to the contralateral side. Characteristically, it remains asymmetric through the course of the disease. Mental stress or movements of another body part (contralateral hand and gait) typically trigger the rest tremor or increase tremor amplitude. Parkinsonian tremor can be also present while maintaining a posture. Postural tremor in PD has been designated as a reemergent tremor, with a latency for the tremor to appear about 9 seconds, which is significantly longer than the latency observed in patients with essential tremor (1 to 2 seconds).

4. Cerebellar tremor is clinically defined by pure or dominant intention tremor. It may be uni- or bilateral. Postural tremor may be present, but no rest tremor. Typically, tremor frequency is below 5 Hz. Cerebellar tremor is often associated with dysmetria (finger-to-nose and heel-to-shin testing maneuvers) and hypotonia. This kind of tremor can be considered a symptomatic tremor produced by any disease that affects the functionality of the cerebellum or its afferent/efferent pathways.

5. Holmes’ tremor is clinically defined by rest and intention tremor, with postural tremor present in many patients. It is mostly unilateral. Postural tremor tends to be more severe than tremor at rest, and intention tremor more severe than the postural tremor. Tremor frequency is usually <4.5 Hz. This is also a symptomatic tremor that occurs after a brainstem, midbrain, or thalamic lesion, when two systems, the dopaminergic nigrostriatal system and the cerebellothalamic system, are lesioned. A variable delay (4 weeks to 2 years) between the lesion and the appearance of the tremor is typical.

Differential diagnosis and evaluation (see cerebellar tremor).

Treatment. Holmes’ tremor and thalamic tremor do not usually respond to pharmacologic treatments. Although the effects of thalamic deep brain stimulation in the ventral intermediate nucleus are incomplete, functional surgery in complex tremor syndromes appears as the only available therapeutic option and provides significant and lasting functional improvement.

6. FXTAS. Over the past decade, it has been shown that premutation carriers (especially males) of the FMR1 mutation (55 to 200 CGG repeats) are at risk of developing the FXTAS. Core clinical features of FXTAS are progressive cerebellar gait ataxia, mild parkinsonism, autonomic dysfunction, peripheral neuropathy, and intention tremor. Postural and rest tremor may be also present. FXTAS is often misdiagnosed as essential tremor and PD. As the diagnosis of FXTAS has substantial implications regarding genetic counseling, it is important to consider FXTAS as a cause of tremor when ataxic symptoms are also present.

Dystonia is a syndrome characterized by excessive, patterned, intermittent or sustained, and sometimes painful muscle spasms that produce abnormal postures or repetitive movements. Dystonic contractions are mainly characterized by the following:

1. Consistent directionality: The movements are patterned and repeatedly involve the same muscle groups.

2. Aggravation by voluntary movement (action exacerbation). Dystonia may be also triggered by particular actions such as writing or playing a musical instrument (task-specific dystonia).

3. Presence of a “sensory trick,” the use of a tactile or proprioceptive stimulus, generally in some particular spot in the same area where the dystonic movements are present, which can improve the muscle contractions.

1. Focal. The abnormal movements affect single body region such as cervical dystonia, blepharospasm, spasmodic dysphonia, oromandibular dystonia, or brachial dystonia.

2. Segmental. The abnormal movements affect two or more contiguous body parts, as in Meige’s syndrome (blepharospasm plus oromandibular dystonia), craniocervical dystonia, or bibrachial dystonia.

3. Multifocal. Two or more noncontiguous body areas are involved.

4. Hemidystonia. The abnormal movements affect one side of the body.

5. Generalized. Abnormal movements are present in the legs (or in one leg and the trunk) plus at least one other area of the body.

1. Early-onset: <26 years.

2. Late-onset: >26 years.

1. Primary, or idiopathic, dystonia.

2. Secondary dystonia.

Dystonia is attributed to basal ganglia abnormalities and to a dysfunction of the cortico-striatothalamo-cortical circuits. Idiopathic dystonia is not associated with any particular structural brain lesion. However, neurophysiologic and neuroimaging techniques have shown a correlation between the co-contraction and overflow of EMG activity of inappropriate muscles, with reduced pallidal inhibition of the thalamus due to lower firing rates, large sensory receptive fields, and irregular discharges in bursts or groups of bursts in neurons of the medial globus pallidus. Supporting the theory of basal ganglia dysfunction, secondary dystonia is mostly observed in patients with lesions of the putamen and connections with the thalamus and cortex.

1. PTD. It refers to those syndromes in which dystonia is the only phenotypic manifestation (except for tremor). In cases of PTD, there is no history of brain injury, no laboratory findings exclusive of genetic tests to suggest a cause for dystonia, no consistent associated brain pathology, and no improvement with a trial of low-dose levodopa. Some of these cases can be attributed to a genetic cause. Early-onset PTD (Oppenheim’s dystonia) is inherited as an autosomal dominant trait with reduced penetrance (30% to 40%). The genetic mutation for the most frequent and severe form of early-onset PTD, named DYT1, was mapped to chromosome 9q34, which encodes
the protein TORSIN, whose function remains unknown. The disorder develops before 26 years of age in nearly all cases. It normally begins in one arm or a leg, and spreads to other limbs and trunk, leading to the most severe generalized form of the disease in most cases. Selective or pronounced craniocervical or orofacial involvement is unusual. Conversely, late-onset PTD (>26 years—DYT4, DYT6) normally involves the upper part of the body (cranial-cervical region) and usually remains focal or segmental. In spite of this archetypical pattern, dystonia may remain localized as writer’s cramp in some patients with early-onset PTD.