Cervical Dystonia: Description, Symptoms

Cervical Dystonia

Description

Cervical dystonia or CD, also known as spasmodic torticollis, is a form of focal dystonia. It is also the most common form of focal dystonia. CD is characterized by abnormal movements or postures of the neck and head. Although CD may become apparent at any age, symptoms usually begin between the ages 20 to 60 years. Women are affected approximately twice as commonly as men are.

Symptoms

Cervical dystonia, the most common form of focal dystonia, is characterized by abnormal squeezing and twisting muscle contractions in the head and neck area. Sustained muscle contractions result in abnormal positions or posturing. Almost all dystonic movements share a directional quality that is typically sustained. Movements may be prolonged or occur in an instant. In general, the dystonias may be classified based on: the age at which symptoms appear; the area or areas of the body that are affected (anatomical distribution); or the cause of the dystonia. CD is classified as a focal dystonia because it typically affects one area of the body (i.e., head and neck).

The dystonic muscle spasms associated with cervical dystonia (CD) may affect any combination of neck muscles. These sustained muscle contractions or spasms result in jerky head movements or periodic or sustained unnatural positioning the head (dystonic posturing). Sideways or lateral rotation of the head and twisting of the neck is likely the most common finding in CD. This is known as rotational cervical dystonia. In addition, tilting of the head is often present. The most common form of torticollis is characterized by turning, flexing, or extending of the neck to the side (laterocollis or lateral flexion). Less commonly, posturing to the front (anterocollis) or back (retrocollis) may also occur. One shoulder may be elevated and displaced forward on the side toward which the chin turns. In addition, there is often mild associated dystonia in the upper arm muscles on the same side (segmental dystonia). There does not seem to be an association between 'handedness' and the direction of the tilt.

Symptoms of CD often worsen while walking or during period of stress. Symptoms typically improve with rest or sleep. In addition, CD is the most common focal dystonia that responds to a sensory trick or geste antagoniste. For example, patients with CD may find that placing a hand on the side of the face, chin, or the back of the head, temporarily alleviates the dystonic posture. Leaning the head back against a chair or placing a hand on the top of the head may also help to relieve CD symptoms. The reason that sensory tricks work for some patients is not fully understood.

Muscle hypertrophy is present in almost all CD patients. Over two-thirds or up to 80% of patients, particularly those with sustained head deviation, have associated neck pain. About 33% to 40% of these patients also experience head tremor (i.e., dystonic tremor), hand tremor, or both. Approximately 20% of patients with CD also have blepharospasm or dystonia in other muscles or in muscle groups of the arm or hand. In addition, about 15% of patients have hand tremor resembling essential tremor.

Evidence suggests that about 10% to 20% of patients with cervical dystonia may have brief, spontaneous remissions (Poewe W, 1992). Almost all affected individuals eventually experience a relapse of symptoms. An additional 10%, particularly patients with an earlier age at symptom onset, may have longer remissions of about two to three years, typically beginning during the first few years following disease onset.

Causes/Genetics

In most cases, the exact cause of CD is usually not known. The condition appears sporadically, in the absence of a documented family history of the disease. In about 10% to 15% of cases, more than one family member may be affected. Several families have been described with autosomal dominant, adult-onset, primary dystonia that is focal in distribution, affecting the neck region. This form of the condition has been called 'familial torticollis.' In one German kindred, the autosomal dominant disorder was mapped to chromosome 18p. This genetic location or locus has been designated as DYT7. However, other kindreds with familial torticollis have been excluded from the DYT7 as well as the DYT1 regions and the responsible gene location has not yet been identified.

In most patients, the role of heredity in primary adult-onset focal/segmental dystonia remains unknown. Some researchers suggest that heredity may be a factor in the development of these dystonias, based upon several findings, such as the following:

• In addition to the kindreds discussed above, familial cases of primary adult-onset focal dystonia have been reported, including cervical dystonia.
• In one study, 25 of 40 non-Jewish individuals with a focal dystonia such as cervical dystonia or writer's cramp had relatives with symptoms of dystonia.
• According to multiple large studies of primary adult-onset focal dystonia, 2% to 15% of patients have had relatives with signs of focal or segmental (but not generalized) dystonia.

Based upon these and other findings, some researchers suggest that primary adult-onset focal dystonias may commonly be transmitted as an autosomal dominant trait with reduced penetrance and variable expressivity. In addition, some investigators speculate that adult-onset primary focal dystonias may represent a localized manifestation of primary generalized dystonia, with the final anatomical distribution reflecting patient age and specific site of onset. Possible support for this theory includes the fact that primary generalized dystonia often begins as a focal dystonia. In addition, primary focal and generalized dystonias are both characterized by effective sensory tricks and both respond similarly to certain medications.

Dystonia that begins in the neck or cranial region rarely results from mutations of the DYT1 gene, indicating that most focal dystonias that do not begin in a limb are probably distinct from primary generalized dystonia. Therefore, whether primary focal and generalized dystonias may be variations of the same disorders or are truly distinct disease entities remains unclear.

Some studies also suggest that focal dystonia may be precipitated by trauma or overuse of the affected region of the body. For example, some researchers theorize that prior trauma may play some role in triggering disease onset in patients who carry a mutated DYT1 gene for DYT1 dystonia. In addition, several studies have suggested a possible association of focal dystonias with prior peripheral trauma. For example, researchers have reported that trauma occurred three to six months prior to symptom onset in approximately 5% to 12% of patients with cervical dystonia.

In some cases, the relationship between trauma and the onset of dystonia is clear when dystonia follows brain injury or severe peripheral trauma. However, in many patients, the relationship is less clear and trauma alone probably would not be sufficient for the development of dystonia. Rather, some research suggests that trauma may play some role in triggering dystonia in those with previously, very mild, undetectable cases-or in patients with an existing, potentially genetic, susceptibility to the disorder. Further research is necessary to determine the various underlying genetic, environmental, or other underlying mechanisms that may play a role in causing the focal dystonias, including cervical dystonia.

Epidemiology

The mean age of symptom onset in patients with cervical dystonia is approximately 41 years. However, onset is variable and may range from childhood to old age. Women are more commonly affected by CD than men, in a ratio of 2:1. Disease remissions may occur in about 20% of patients, usually during the first few years. The longer the duration of the patient's disease, the less likely they are to experience a remission.

Due to the variability of associated symptoms and disease severity and the fact that some patients with mild cases of CD may remain undiagnosed, it is difficult to determine the specific frequency of primary dystonia in the general population. However, according to a 1988 study conducted in Rochester, Minnesota, the frequency was estimated to be 29.5 individuals per 100,000 for focal dystonias.

There are few epidemiological studies on dystonia and its various forms. A large European study, reported in the literature in 2000, estimated the crude annual period prevalence rate for primary dystonia (for 1996-1997) at 152 per million. Of the primary dystonias, focal dystonia had the highest relative rate at 117 per million. The prevalence rates for cervical dystonia were estimated at 57 per million individuals. The relative rates, adjusted for age, were substantially higher in women than in men for focal dystonias such as CD. The exception to this was writer's cramp. Warner T et al. point out that these estimates should be viewed as an underestimation of the true prevalence of dystonia. Their estimates are seen as conservative due, in part, to under-ascertainment of cases.

Pathophysiology

No consistent or specific changes in brain tissue or function have been seen in individuals with cervical dystonia. The basic underlying defect or defects in this disorder remain unknown. However, investigators suggest that the primary dystonia, as well as dystonia-plus syndromes, probably result from abnormalities in the activity of certain neurotransmitters, such as an imbalance of dopamine transmission, within the basal ganglia. Neurotransmitters are naturally produced chemicals that transfer nerve impulses across synaptic gaps, thus enabling nerve cells to communicate. The basal ganglia consist of specialized nerve cell clusters deep within the brain that organize motor behavior.

Thus, in some patients, a primary focal dystonia such as CD may be considered neurochemical in origini.e., neurochemical disorders that do not appear to result in structural neurodegenerative changes. In contrast, heredodegenerative disorders are usually hereditary disorders in which structural neuronal degeneration may be associated with neurochemical abnormalities. An underlying neurochemical basis for many dystonias may be suggested by multiple factors, including evidence that secondary dystonia may result from treatment with the dopamine precursor L-dopa (such as used for treatment of Parkinson's disease) or therapy with dopamine receptor blockers (antagonists).

Electrophysiology (CD and other forms of dystonia)

Electromyography (EMG) is a diagnostic test in which the electrical activity of voluntary (skeletal) muscles is measured at rest and during voluntary action. In patients with dystonia, EMG may reveal little or no activity at rest or prolonged bursts of electrical activity with overflow to muscles that are not normally involved. More specifically, abnormal EMG patterns at rest may include any of the following:

• Relatively long spasms that result in abnormal, sustained postures
• Repetitive bursts of electrical activity that are mid-range in length (i.e., approximately 200 to 500 milliseconds). (Note: EMG bursts usually do not last longer than approximately 100 milliseconds.)
• Irregular bursts or jerks that are short (i.e., less than 100 ms), resembling those associated with myoclonus.

In addition, any of the above EMG patterns may also occur with voluntary movements. Patients with dystonia usually have difficulty selectively initiating movement of appropriate muscles required for certain voluntary actions and experience simultaneous contraction of antagonist muscles. In addition, there is a decrease in or loss of the active inhibition of antagonist muscles that normally occurs with voluntary contraction of agonist muscles. Some researchers suggest that decreased inhibition leading to an 'overflow' of movement may result from loss of inhibition at the level of the cerebral cortex, brainstem, and spinal cord via the basal ganglia and its pathways. (The basal ganglia cells of origin of the inhibitory pathways are under the control of the activities of the neurotransmitter dopamine.) Such a theory may potentially explain how dystonia may result from or be triggered by different mechanisms. According to such a theory, significant loss of inhibition potentially leading to dystonia may result from lesions of certain areas of the brain; specific genetic abnormalities; or a genetic predisposition that may be triggered by environmental factors, such as abnormal sensory input resulting from repeated use and/or trauma of the affected body part.

There is some evidence suggesting that certain abnormalities in the brain's ability to process sensory information may also play some role in causing dystonia by altering brain motor control. According to researchers, this possibility is supported by various factors, including the 'sensory tricks' observed in many patients with cervical dystonia and the fact that some patients may develop certain sensory symptoms prior to the development of CD. Further research is needed to learn more about the potential causative role of loss of inhibition, sensory dysfunction, peripheral trauma, and/or other mechanisms in dystonia.

Diagnosis

• General physical and neurologic examinations
• Evaluation of the nature of the dystonia, including
• Apparent age at symptom onset
• Bodily distribution
• Disease progression
• Whether dystonia occurs with specific actions
• If it is characterized by 'overflow'
• If it is present at rest
• Whether certain 'sensory tricks' temporarily suppress dystonic movements

The examiner may also attempt to conduct passive movements of the affected bodily region, carefully feel (palpate) contracting muscles, and/or request that a patient adapt various positions or postures with the affected area. Such methods may be necessary for accurate diagnosis, appropriate assessment of the nature of dystonia, and localization of involved muscles (e.g., for those who may be appropriate candidates for therapy with botulinum toxin). Such evaluation may be documented by videotaped recordings. For those patients with suspected laryngeal dystonia, voice assessment is typically documented on voice recordings.

Additional evaluations may include assessment by a speech-language pathologist, when appropriate, physical or occupational therapists, or genetic counselors.

• A thorough patient history to help determine or exclude causative factors potentially associated with cervical dystonia and other forms of dystonia, such as exposure to certain toxins; peripheral, head, or spinal trauma; certain infections or inflammatory conditions of the brain; etc.
• A detailed family history
• Electrical recording techniques, such as electromyography (EMG); nerve conduction velocity tests; or other methods (e.g., reflex studies).
• Biopsies. In selected patients, diagnostic assessment may include surgical removal and microscopic evaluation (biopsy) of small samples of skin, muscle, and/or nerve tissue.
• Thorough neurologic evaluations to help confirm or exclude the presence of other neurologic signs that may suggest secondary dystonias, dystonia-plus syndromes, or heredodegenerative disorders. Such neurologic signs may include certain eye (ocular) abnormalities (e.g., optic atrophy, retinal abnormalities); parkinsonism; myoclonus; impaired coordination of voluntary movements (ataxia); spasticity; muscle weakness; dementia; seizures; and/or other findings.

For certain patients with adult-onset focal dystonia such as cervical dystonia, which is presumed to be primary (e.g., based upon thorough clinical examination, a complete patient and family history, nature of the dystonia, absence of certain signs upon examination, etc.), experts indicate that extensive laboratory or neuroimaging studies may not be necessary.

Approaches to Treatment

Chemodenervation

Botulinum Toxin Type B (BTX-B) for Cervical Dystonia

On December 11, 2000, a botulinum toxin type B product (MYOBLOC) was approved by the FDA in the United States as a treatment of patients with cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia. MYOBLOC is the U.S. trade name for Elan Biopharmaceuticals' botulinum toxin type B product. This product also received marketing authorization from the European Union's Committee for Proprietary Medicinal Products and is available there as Neurobloc. MYOBLOC is available as a refrigerated, liquid formulation, which may be further diluted (with normal saline). It is an acidic solution with a Ph of 5.6. It is provided as a sterile injectable solution at a concentration of 5,000 U per 1 mL and a pH of 5.5. Vials contain 0.5 mL (2,500 U), 1.0 mL (5,000 U), or 2.0 mL (10,000 U). Because vials are actually overfilled, each vial contains slightly more toxin than these indicated volumes.

The duration of effect is approximately 12 to 16 weeks. The potential adverse effects of MYOBLOC/Neurobloc are similar to those seen after injections of botulinum toxin type A and may include difficulty swallowing and dry mouth. These effects are usually short-lived and reversible.

Approaches to Treatment with Botulinum Toxin Type B

The approach to treatment with botulinum toxin type B involves

• Establishment of treatment goals
• Determination of appropriate dosing
• Appropriate muscle selection for injection sites. (There are 52 muscles involved in cervical function, such as controlling the rotation, extension, and tilting of the head.)
• Appropriate selection of muscles based on patient's pain and the location of the painful area(s)
• Further consideration of dose and concentration for each muscle
• Possible administration into multiple sites within each affected muscle
• Follow-up with the physician regarding benefits or adverse effects

MYOBLOC is injected directly into the dystonic muscle. The injected solution weakens the muscle by 'chemically disconnecting' the muscle from its nerve supply and the chemical messages that it sends to the muscle.

The efficacy of MYOBLOC in the treatment of cervical dystonia has been demonstrated in three pivotal double-blind trials. Lew et al. enrolled 122 patients with idiopathic cervical dystonia (CD) in a single-treatment, double-blind, placebo-controlled safety and efficacy study of botulinum toxin type B. Both botulinum toxin type A-responsive and resistant patients were enrolled. Patients received intramuscular injections of 2,500 U, 5,000 U, or 10,000 U of botulinum toxin type B or placebo. The primary outcome measure of efficacy was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), with measurement of total score at four weeks following drug administration. TWSTRS is a validated rating scale for determining the efficacy of botulinum toxin treatment. Secondary measures of efficacy were TWSTRS-Severity, -Disability, and -Pain subscale scores, as well as Analog Pain Assessment, Investigator Global Assessment, Patient Global Assessment, and Sickness Impact Profile scores. Duration of effect was estimated with an intent-to-treat analysis of responders. Safety measures included clinical parameters, laboratory tests, and adverse events.

Improvement significantly greater than placebo was reported in all active treatment arms, with magnitude of improvement increasing with escalating doses. The best response was seen in patients receiving 10,000 Units. These patients experienced a five-fold greater improvement than placebo-treated patients (p < 0.0005). Dry mouth (27%) and dysphagia (33%) were the most common adverse events seen in patients at the highest dose, versus 0% dry mouth and 3% dysphagia in the placebo group. Injection-site pain occurred in 17% of toxin-treated patients versus 10% of placebo-treated patients. The authors concluded that, at the doses tested, botulinum toxin type B is safe, well tolerated, and efficacious in the treatment of cervical dystonia.

Brin et al. enrolled 77 botulinum toxin type-A resistant CD patients into a 16-week, single-treatment, double-blind, placebo-controlled trial of botulinum toxin type B After resistance to therapy was confirmed with the frontalis-type A test, patients received either placebo or 10,000 U of the type B toxin, which was administered in two to four muscles. TWSTRS-Total score was the primary efficacy measurement. Patients were assessed at baseline and at weeks 2, 4, 8, 12, and 16. Additional assessment measures included the Patient Global Assessment of Change, Principal Investigator Global Assessment of Change, Patient Analog Pain Assessment, and adverse events.

Improvements in severity, disability, and pain were documented in the botulinum toxin type B-treated group. TWSTRS-Total scores were improved in this group at 4 weeks (p = 0.0001), 8 weeks (p = 0.0002), and 12 weeks (p = 0.0129). All three visual analog scales demonstrated improvements at 4 weeks (p < 0.001). A Kaplan-Meier analysis supported a duration of effect of 12 to 16 weeks in the active group. Dry mouth and dysphagia were reported more commonly in the botulinum toxin type B group. The authors concluded that botulinum toxin type B is safe and efficacious for the management of patients with type A-resistant cervical dystonia, with an estimated duration of treatment effect of 12 to 16 weeks.

Brashear et al. enrolled 109 botulinum toxin type A-responsive patients with CD in a 16-week, randomized, multi-center, single treatment, double-blind, placebo-controlled trial of botulinum toxin type B. Placebo, 5,000 U, or 10,000 U of botulinum toxin type B toxin was administered to two to four muscles. TWSTRS-Total score at week 4 was the primary efficacy measure. Clinical assessments and adverse events were recorded at baseline and at weeks 2, 4, 8, 12, and 16.

The mean improvement in the TWSTRS-Total scores in each group at week 4 was 4.3 (placebo), 9.3 (5,000 U), and 11.7 (10,000 U). For the prospectively defined primary comparison (10,000 U versus placebo), highly significant differences were noted for the TWSTRS-Total at baseline to week 4 (p = 0.0004) and for supportive secondary Patient Global Assessment at baseline to week 4 (p = 0.0001). Improvement in pain, disability, and severity of CD occurred for patients who were treated with botulinum toxin type B when compared with placebo-treated patients. Overall, improvements associated with botulinum toxin type B treatment were greatest for patients who received the 10,000 U dose. The duration of treatment effect was 12 to 16 weeks for both doses of toxin. The authors concluded that botulinum toxin type B is safe and efficacious at 5,000 U and 10,000 U for the management of patients with type A-responsive cervical dystonia.

Dosing of Botulinum Toxin Type B

It is important that patients discuss previous treatments for cervical dystonia, particularly injections with other serotypes of botulinum toxin, such a botulinum toxin type A (BOTOX or Dysport). Patients are urged to share copies of their medical records so that their treating physicians are able to determine previous drug and chemodenervation agents and the doses given. Since the dosing for botulinum toxin type B product is different from that of botulinum toxin type A products, and indeed between different products of the same serotype, physicians will make the appropriate adjustment in the number of units required for treatment with botulinum toxin type B. One method for accessing a patient's response to treatment is use of the TWSTRS rating scale.

Injection of Botulinum Toxin Type B

During the administration of botulinum toxin type B, a relatively small needle is placed into the target muscle. In large or accessible muscles, confirmation of appropriate placement of the injection into the target muscle may be achieved by feeling the muscle. In small or deep muscle groups, electromyography (EMG) or electrical stimulation may be required to confirm appropriate placement.

Small muscles may be injected in only one or two sites. Larger muscles may require three to four injection sites. Most individuals are able to tolerate these small needle punctures; however, if necessary, local anesthetic cream or sedation may help ease discomfort or anxiety associated with injection. This may be particularly useful for children who are receiving injections.

Vials of MYOBLOC may be stored at 2 degrees to 8 degrees Centigrade for up to 21 months. In order to preserve the integrity of the toxin, vials should not be frozen or shaken. MYOBLOC may be diluted with sterile saline (without preservative). Because the volume in the vials is greater than the nominal volume, dilution should be performed in the syringe, not in the vial. Diluted toxin should be used within four hours.

Safety of Botulinum Toxin Type B

The safety and efficacy of MYOBLOC were demonstrated in several studies, including two, 16-week, double-blind, placebo-controlled clinical trials. Botulinum toxin type B is an effective treatment for cervical dystonia patients who respond to botulinum toxin type A as well as in patients who had develop resistance to botulinum toxin type A. Botulinum toxin type A and botulinum type B have slightly different chemical structures and their primary mechanisms of action also differ.

Antibodies and Botulinum Toxin Therapy

In some individuals treated with botulinum toxin, antibodies may develop, bind to the toxin, and inactivate it. This renders botulinum toxin ineffective in weakening muscle contractions associated with dystonia. It is estimated that approximately five percent or up to possibly 20 percent of individuals with cervical dystonia who have been treated regularly with relatively higher doses of botulinum toxin type A develop antibodies. Once a patient forms antibodies to a particular serotype of botulinum toxin (immunoresistance), further injections of that particular serotype of botulinum toxin are typically ineffective. Physicians should, therefore, use the smallest amount of toxin necessary to achieve therapeutic benefit and extend the time interval between treatment sessions as long as possible, with at least three months between treatments.

On occasion, a patient may not respond to therapy with botulinum toxin. So-called 'primary non-responders' are patients who do not respond to their first injection of toxin. Secondary non-response may occur because of immunoresistance or as the result of a technical problem, such as an inappropriate site of injection into the wrong muscle, a dose that is inadequate to provide a clinical effect, or disease progression. The toxin may weaken the muscle; however, the degree of relaxation may not provide symptomatic relief for the patient. In addition, some patients on combination therapies for segmental or generalized dystonias may fail to take their oral medications, leading to a general increase in symptoms (masking the local effects of botulinum toxin). If failure to respond continues, it is possible that the patient has antibody-mediated resistance (immunoresistance). When a patient develops resistance to a botulinum toxin type A, MYOBLOC/Neurobloc, a botulinum toxin type B product, has been shown to be effective for the treatment of pain and disability of CD.

Antibody-based resistance is a significant concern in botulinum toxin therapy. No studies have been published thus far concerning development of resistance in patients receiving MYOBLOC. An open-label extension trial was conducted on 446 patients from the three studies described above as well as others who opted to continue to receive MYOBLOC. Serum samples were examined for presence of anti-toxin antibodies using the ELISA. Serum from patients with positive ELISA tests was then tested in a mouse neutralization assay (MNA). Interim analysis showed after 6 months of treatment, the probability of a positive ELISA test was 20%, while the probability of a positive MNA result was 0%. At one year, these figures rose to 36% and 10%, and at 18 months, to 50% and 18%. Twelve MNA-positive patients withdrew from the study. The probability of withdrawing from treatment was no higher for MNA-positive patients than for MNA-negative patients.

The complex issues involved in the development of antibodies to botulinum toxins are not fully understood. The development of antibodies or immunogenicity in a patient receiving botulinum toxin treatment may be related to the relative amount of protein in the injected toxin as well as the quality of the protein (neurotoxin complex) in the product. Additional research studies are required to increase the understanding of immunogenicity. It is important that patients work with their physicians to set appropriate treatment goals and tailor the course of treatment to meet these goals. There is no formal 'recipe' that works for every patient with CD. Each individual is unique and responds differently to botulinum toxin therapy.