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REVIEW ARTICLE

Overview of the Diagnosis and Treatment of Stuttering

Gerald A. Maguire

1,2,3 *

, Christopher Y. Yeh

1

, Brandon S. Ito

1

1Department of Psychiatry, University of California, Irvine School of Medicine, Orange, CA, USA 2Office of Medical Education, UCI School of Medicine, Orange, CA, USA

3Kirkup Center for the Medical Treatment of Stuttering, UCI School of Medicine, Orange, CA, USA

a r t i c l e i n f o

Article history: Received: Jan 3, 2012 Revised: Feb 1, 2012 Accepted: Feb 1, 2012 KEY WORDS:

dopamine hypothesis of stuttering; medication;

stuttering

Stuttering is a speech disorder defined by frequent prolongations, repetitions, or blocks of spoken sounds and/or syllables, as well as anxiety and cognitive avoidance. Stuttering is a very common disorder, and research now indicates that it is likely a multifactorial process with a physiologic etiology. Recent advances in thefield of stuttering now provide insight into novel treatment strategies to help guide the practicing clinician. In addition to considering the upcoming revision to the Diagnostic and Statistical Manual of Mental Disorders criteria, comprehensive treatment should address all aspects of this disorder, as the optimal treatment of stuttering involves a multidisciplinary approach.

CopyrightÓ 2012, Taipei Medical University. Published by Elsevier Taiwan LLC. All rights reserved.

1. Introduction

Stuttering is a multifactorial speech disorder defined by frequent prolongations, repetitions, or blocks of spoken sounds and/or syllables. It is a common disorder affecting about 1% of the adult population1and is classified in the Diagnostic and Statistical Manual of Mental DisordersdFourth Edition as an Axis I disorder (Table 1). Characteristics of stuttering include repetition of sounds or sylla-bles, sound prolongations, interjection, broken words, blocking of sounds, word substitutions, or excessive physical tension during speech production.2Other coexistent symptoms may include facial grimacing, tremors of muscles involved in speech, and eye blinks as well as avoidance of words or situations which exacerbate stut-tering episodes.3,4

The most common form of stuttering is developmental stut-tering, which begins in childhood. A total of 80e90% of develop-mental stuttering begins by 6 years of age and affects about 5% of children.5,6Spontaneous recovery occurs in about 75% of individ-uals.7 Rare cases of acquired stuttering do occur and begin in adulthood, but are related to secondary causes such as medications, brain trauma, or stroke.8In about 60% of children who stutter, the symptoms will remit by 16 years of age. But many cases persist into adulthood, and given the importance of communication in the development of a child, treatment of stuttering in children requires early intervention.9

The American Psychiatric Association is currently in the process of modifying the classification and description of stuttering for Diagnostic and Statistical Manual of Mental DisordersdFifth Edition (Proposed Revision): Childhood Onset Fluency Disorder, due for publication in May 2013.10Several proposals include changing the diagnostic label of“Stuttering” to “Child Onset Fluency Disorder,” deletion of criterion of interjections, inclusion of avoidance and/or anxiety around speaking situations related to stuttering, and improved distinction between childhood-onsetfluency disorder or stuttering from other adult-onset forms (Table 2). Such changes are proposed while recent advances in the knowledge of stuttering lead toward a neurophysiologic basis. Improved clarification of the DSM criteria will allow individuals who stutter to have greater access to comprehensive care including speech and cognitive therapies, and emerging pharmacologic treatments.10

2. Etiology

For centuries, stuttering was believed to involve abnormalities in the tongue or larynx. But treatments that focused on the tongue or larynx have not demonstrated consistent efficacy in improving stuttering symptoms. It was the pioneering work of Orton11and

Travis,12who postulated that stuttering may arise from abnormal cerebral activity, which signaled a change in the understanding of stuttering. Research now indicates that stuttering is likely a multi-factorial process with a physiologic etiology.

Genetic factors are thought to be involved in many cases of stuttering, accounting for about 50e80% of stuttering cases based on twin and family studies.13 Pairwise concordance for mono-zygotic same-sex twins is significantly greater than in fraternal * Corresponding author. Gerald A. Maguire, Department of Psychiatry, University

of California, Irvine School of Medicine, 101 The City Drive, Building 3, Route Number 88, Orange, CA 92868, USA.

E-mail: Gerald A. Maguire <gerald.maguire@uci.edu>

Contents lists available atSciVerse ScienceDirect

Journal of Experimental and Clinical Medicine

j o u r n a l h o m e p a g e : h t t p : // w w w . j e c m - o n l i n e . c o m

1878-3317/$ e see front matter Copyright Ó 2012, Taipei Medical University. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.jecm.2012.02.001

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pairs (63% vs. 19%, respectively).14Stuttering also has a male/female ratio of about 4:1, with female stutterers much more likely to have spontaneous remission with age.13This sex discrepancy results in up to 80% of adult stutterers being male.15

Acquired stuttering also occurs, but is much less common and is often the result of brain trauma or medication.3Adults who stutter are also at an increased risk for both mood16 and anxiety disorders.17,18

Several recent studies have focused onfinding a genetic basis for stuttering. In a study of 112 individuals, the presence of the C allele at rs6277 in the dopaminergic DRD2 gene was associated with increased susceptibility to the disorder.19 Similarly, a report on a case with a complex set of speech and language difficulties including stuttering by Petrin et al20 found that deletions and disruptions in genes are involved in the cause of language and speech disorders. More recently, stuttering has been associated with mutations in genes involved in lysosomal metabolism in

certain individuals. Mutations in three genes on chromosome 12 that disrupt the lysosomal targeting pathway which generates the mannose 6-phosphate signal have been identified. Although the mutations can only be identified in less than 10% of cases of familial stuttering, their identification provides new insight and direction for future studies.21

One recent case report suggests stuttering as a pediatric auto-immune neuropsychiatric disorder associated with streptococcal infections (PANDAS),22 which has been described in Tourette syndrome to share many clinical symptoms with stuttering. The hypothesis is that the antibodies created tofight the streptococcal infection cross-react with the developing basal ganglia, the region of the brain implicated in stuttering etiology.23e25 While the recovery in this case may have been spontaneous and unrelated to antibiotic therapy, further research are indicated into this possible etiology.22,26

3. Brain imaging studies

Imaging studies have implicated a number of brain regions involved in the process of stuttering. While no single region of the brain has been identified as the source of developmental stuttering, imaging studies have implicated brain asymmetry, extra sulci, or reduced white matter changes involved in areas involved in speech or articulation.27

Thefirst positron emission tomography (PET) study in stuttering (using [18F]deoxyglucose) reported abnormal glucose metabolism in speech cortical areas and the striatum in stuttering individuals. The speech cortical areas normalized under induced fluency, but the basal ganglia remained low.28Studies using PET scans of individuals with moderate to severe developmental stuttering also showed significantly higher 6-fluorodopa uptake in the medial prefrontal cortex, deep orbital cortex, insular cortex, extended amygdala, auditory cortex, and caudate tail compared to controls.29 Sommer et al30 found structural abnormalities in the left hemispheric speech areas to be implicated in stutterers. Their findings also suggest that persistent developmental stuttering results from disturbed timing of activation in speech-relevant brain areas, meaning that right hemisphere overactivation may reflect a compensatory mechanism analogous to right hemisphere acti-vation in aphasia.30

One study comparing cortical activation sequences in 10fluent speakers and nine developmental stutterers showed clear differ-ences in cortical activation patterns, both in the evoked responses, time-locked to word presentation and mouth movement onset, and in task-related suppression of 20-Hz oscillations. Several of the findings included differences in sequence of activation of articula-tory programming and motor preparation, activation and silence of the right motor/premotor cortex during speech production, hemi-sphere dominance in suppression of motor cortical rhythms, and activity level of the right frontal cortex during speech production. The authors suggested that the findings may reflect imprecise functional connectivity within the right frontal cortex and incom-plete segregation between the adjacent hand and mouth motor representations in stutterers during speech production.31

In another study using both structural and functional imaging of 12 patients with developmental stuttering, Watkins et al27in 2008 found bilateral structural abnormalities of the ventral premotor cortex, along with underlying reduced functional white matter integrity, which the authors argue are critical regions involved in the integration of motor planning and sensory feedback to produce fluent speech. In this study, patients also displayed marked over-activity in the midbrain, most likely involving the basal ganglia, lending further support for the central role of the dopaminergic system in the development of stuttering.25

Table 1 DSM-IV-TR diagnostic criteria for stuttering Stuttering

A. Disturbance in the normalfluency and time patterning of speech (inappropriate for the individual’s age), characterized by frequent occurrences of one or more of the following:

1. Sound and syllable repetitions 2. Sound prolongations 3. Interjections

4. Broken words (e.g., pauses within a word)

5. Audible or silent blocking (filled or unfilled pauses in speech) 6. Circumlocutions (word substitutions to avoid problematic words) 7. Words produced with an excess of physical tension

8. Monosyllabic whole-word repetitions (e.g.,“I-I-I-I see him”) B. The disturbance influency interferes with academic or occupational

achievement or with social communication.

C. If a speechemotor or sensory deficit is present, the speech difficulties are in excess of those usually associated with these problems.

Coding note: If a speech-motor or sensory deficit or a neurological condition is present, code the condition on Axis III.

DSM-IV-TR: Diagnostic and Statistical Manual of Mental DisordersdFourth Edition (Text Revision).

Table 2 DSM-5 proposed revision of diagnostic criteria for childhood onsetfluency disorder (stuttering)

Childhood Onset Fluency Disorder

A. Childhood onset Fluency Disorder, also referred to as stuttering, is diagnosed when disturbances in the normalfluency and time patterning of speech are inappropriate for the individual’s age and language skills, persist over time (in most cases), and are characterized by frequent and marked occurrences of one or more of the following:

1. Sound and syllable repetitions

2. Sound prolongations of consonants as well as vowels 3. Broken words (e.g., pauses within a word)

4. Audible or silent blocking (filled or unfilled pauses in speech) 5. Circumlocutions (word substitutions to avoid problematic words) 6. Words produced with an excess of physical tension

7. Monosyllabic whole-word repetitions (e.g., "I-I-I-I see him") 8. Anxiety about symptoms 1e8 leading to avoidance associated with

speaking situations.

B. The difficulties with speech fluency result in functional limitations in effective communication, social participation, academic performance, or occupational performance, alone or in any combination.

C. Exclude dysfluency associated with neurological insult (e.g., stroke, tumor, trauma) or conversion reaction and malingering. Afluency disorder may occur as primary or coexist with other communication disorders or any other disorder not excluded.

D. Symptoms must be present in early childhood (but may not become fully manifest until speech, language, communication, or social demands exceed limited capacities).

DSM-V: Diagnostic and Statistical Manual of Mental DisordersdFifth Edition (Proposed Revision, Updated December 9, 2010). Retrieved December 20, 2011.

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Brown et al32 conducted an activation likelihood estimation meta-analysis of imaging studies compared stuttered andfluent speech production in adults. They found that motor areas to be overactivated in stuttering include primary motor cortex, supple-mentary motor area, cingulate motor area and cerebellar vermis. Additionally, stutterers showed anomalous right-laterality in the frontal operculum, Rolandic operculum, and anterior insula. The authors further proposed the phenomenon of efference copy as a unifying account of the pattern activation revealed within their analysis, arguing that it provides the basis for a stuttering system model that is testable and should help advance the understanding and treatment of this disorder.32

Recent functional magnetic resonance imaging (fMRI) studies have looked at neural circuits involved in atypical planning and disrupted execution of speech commonly involved in patients who stutter. Lu et al33found that atypical planning occur in the bilateral inferior frontal gyrus and right putamen, and that their atypical execution of speech is evident in their activations in the right cerebellum and insula, left premotor area, and angular gyrus.

Transcranial magnetic stimulation has also been used to study the physiologic basis of stuttering. One recent study found that in persistent stuttering, intracortical excitability of the primary motor tongue representation is altered with a deviant time course for inhibitory activity in the right hemisphere and reduced paired-pulse facilitation. The results raise the possibility that changes in intracortical networks mediated by altered GABAergic regulations may be associated with persistent stuttering.34

4. The dopamine hypothesis of stuttering

Stuttering is likely related to abnormal elevations of cerebral dopamine activity. Studies with stimulant medications which increase dopamine activity have shown that they increase stutter-ing symptoms.35 In addition, the striatal hypometabolism in stuttering seen in PET imaging may be the result of a hyper-dopaminergic state. Wu et al29 investigated the dopamine hypothesis of stuttering by measuring the presynaptic dopamine levels in individuals who stutter, and showed that these individuals have 50e200% higher levels of dopamine activity than controls. As dopamine is an inhibitor of striatal metabolism, elevated dopamine provides an explanation for the striatal hypometabolism seen in stuttering.28

An increasing amount of research has implicated stuttering as a disorder of the central nervous system, specifically systems involved in regulating dopamine levels within the brain.25 The dopamine hypothesis is also supported by research in which patients with developmental stuttering experience worsened stuttering when given dopamine agonists such as levodopa.36 Clinical trials investigating dopamine antagonists as a treatment for stuttering have providedfindings supporting the central role of dopamine in the etiology of stuttering. Dopamine antagonists haloperidol,37tiapride,38risperidone,39and olanzapine40have all been shown to induce significant improvement of stuttering compared to placebo.

The dopamine hypothesis is also supported by pharmacologic studies of tic disorders. Given the well-documented association between stuttering and tic disorders, it has been proposed that both share a common pathology.41 Studies using the anti-dopaminergic medication aripiprazole have shown effectiveness in reducing motor tics in both patients with developmental stutter-ing42and children and adolescents with a primary tic disorder.43

Lan et al19 recently found evidence supporting a correlation between dopaminergic genes and stuttering among Han Chinese. Their case-control study showed the C allele at rs6277 in DRD2 gene is associated with increased susceptibility to the disorder, while the

T allele is protective. They also found the haplotype 939 T/957 T to be protective factor.19

Alm’s232004 review of possible relations between stuttering

and the basal ganglia circuits examined pharmacologic trials, lesion studies, brain imaging, genetics, and developmental changes of the nervous system, which supported the proposed role of the basal gangliaethalamocortical motor circuits through the putamen in stuttering.

Giraud et al44reported a correlation between severity of stut-tering and activity in the basal ganglia and showed that this activity is modified by fluency shaping therapy through long-term therapy effects that reflect speech production improvement. The model of dysfunction in stuttering and possible repair modes further impli-cates the neural connections between the motor cortex and basal ganglia in speech motor functions.44

Recent studies with Pagoclone sheds new light on the dopamine hypothesis. It is currently unclear how Pagoclone, a selective gamma-aminobutyric acid A (GABAA) partial agonist, benefits

stutterers, but may be related to dopamine/GABA interactions in the basal ganglia15or to changes in intracortical networks mediated by altered GABAergic regulations.34

5. Historical approaches to treatment

In the past, approaches to treatment of stuttering reflected various competing theories on the etiology of stuttering. For many centu-ries, treatment modalities focused on stuttering as an abnormality of the tongue or larynx. More recent treatment modalities are based on behavioral principles intended to allow patients to produce morefluent speech while alleviating anxiety associated with disturbed speech production. Examples include fluency shaping and stuttering modification, where patients attempt to reduce tension. But research on intensive therapeutic modification therapy has failed to produce robust results, as therapeutic benefits have been reported to be limited and temporary.45

6. Pharmacologic treatments

Many medications have been tried in the treatment of stuttering, although at the time of this review, none have been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of stuttering. The most promising medications thus far have been antidopaminergic agents.46Pagoclone, a GABAApartial

agonist, has also shown favorable results.15

Research from imaging studies suggests that people who stutter exhibit hypometabolism of the striatum and increased dopamine activity.29This evidence provides a plausible mechanism as to how dopamine antagonists decrease stuttering by increasing striatal metabolism by blocking D2receptors in the striatum.47

Pharma-cological trials on medications that lower dopamine activity have consistently shown replicated efficacy in improving stuttering. Although they also exhibit sedating qualities, it is likely that their demonstrated efficacy in stuttering is related to their effects on dopamine and not to merely an antianxiety or sedating effect.46

Other agents have been tried with limited efficacy. Limited research with calcium-channel blocking medications such as verapamil, have shown limited efficacy in stuttering.48,49But such

calcium-channel blocking medications may exert a mild antidop-amine effect. Trials of serotonin-selective reuptake inhibitors50and benzodiazepines46have not yielded positive results. Benzodiaze-pines and barbiturates, which are anxiolytics that are also highly sedating, have been found to have no beneficial effects over placebo in the treatment of stuttering.46Histamine blocking agents have also not shown efficacy in stuttering in previous studies.51

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6.1. Haloperidol

Many studies with haloperidol, a conventional dopamine antago-nist and antipsychotic, showed that this medication can improve fluency in individuals who stutter. But long-term compliance with haloperidol in stutterers is poor given its drawbacks: dysphoric side effects, sexual dysfunction, extrapyramidal concerns, and risks of tardive dyskinesia.46Early hypotheses surrounding the potentially beneficial effects of haloperidol in the treatment of stuttering were based on its effect on the dopaminergic system and studies showing the efficacy in haloperidol in the treatment of Tourette’s syndrome.37

In Rosenberger et al’s early double-blind crossover study on the use of haloperidol in the treatment of stuttering,8patients show

clinical improvement in percentage of time dysfluent. But this improvement is significant only for patients who have been greater than 30% dysfluent at baseline.37

Murray et al52performed another double-blind crossover study of 26 adults with haloperidol, and showed that almost all patients improved significantly in terms of number of dysfluencies, speed of speaking, and reduced secondary “struggle” while speaking. Nevertheless, only one out of out 26 patients decided to continue taking the medication after a year, and nearly one-third did not complete the 3-month trial due to the medication’s adverse side effects.52

6.2. Risperidone

A newer generation dopamine antagonist with a side effect profile more favorable than haloperidol, risperidone, has been shown to improve stuttering symptoms (0.5e2 mg/day) in a double-blind, placebo-controlled study. This second-generation (atypical) anti-psychotic (SGA) drug was generally well tolerated, but long-term compliance is hindered by prolactin-related side effects such as sexual dysfunction, galactorrhea, amenorrhea, and dysphoria.39,53 Dysphoria with risperidone has also been reported to occur with its use in Tourette’s syndrome, which shares many similarities to stuttering.54

In a double-blind, placebo-controlled study in the treatment of developmental stuttering in 16 adults, those in the treatment arm had a significant decrease in percentage of syllables stuttered, time stuttering as a percentage of total time speaking, and overall stut-tering severity.39According to a recent case report, treatment with

risperidone also has the added benefit of reducing tic-like motor behaviors in a patient with severe persistent developmental stuttering.55

6.3. Olanzapine

Olanzapine is another newer SGA psychotropic medication that has dopamine blocking properties with fewer prolactin-related side effects. Olanzapine acts as a D2receptor antagonist with additional

antagonist activity at serotonergic receptors. Olanzapine possesses a different side-effect profile than risperidone, with a lower inci-dence of extrapyramidal side effects and hyperprolactinemia, but greater effects on weight gain and triglyceride elevation.56

In Maguire et al’s40double-blind, placebo-controlled trial of 24

adults with developmental stuttering, olanzapine (2.5e5 mg) significantly reduces stuttering symptoms compared to placebo. The degree of improvement was deemed“clinically significant” on active medication by both the patient and the clinician as rated by the Clinical Global Improvement scale. Positive effects of the medication extended to natural speaking situations as measured by the Subjective Screening of Stuttering and Clinical Global Improvement scale. The medication is well tolerated with some

degree of weight gain, without prolactin-associated side effects. Compliance is also high, with all participants electing to enter the open-label phase of the protocol. Of note, for many participants in the open-label extension, stuttering symptoms continued to improve over 6 months to 1 year (or maybe longer), suggesting that an adequate “treatment trial” should be measured in months instead of days or weeks.40

Case reports suggest that olanzapine may also be equally effective and tolerated in the child and adolescent population57and in cases of acquired neurogenic stuttering.58

6.4. Asenapine

Asenapine is a new SGA associated with less weight gain than other atypical antipsychotic medications.59 Maguire et al60 reported three cases of adults with stuttering who responded well to ase-napine (5e10 mg) with good tolerability. Each case resulted in improvedfluency, but no formal measures of fluency were taken. A common side effect in each case was sedation. One patient reported a 4.5-kg (10 lb) weight increase, while the other two experienced none. Theses case reports suggest that asenapine may be an effective and well-tolerated medication for the treatment of stut-tering, warranting further investigation.60

6.5. Aripiprazole

Aripiprazole is a combined D2and 5-HT1Areceptor partial agonist

and 5-HT2Areceptor antagonist. One case report published by Tran

et al42 described its use (5e15 mg) in treating an adult with developmental stuttering, but further research is required. 6.6. Pagoclone

Pagoclone is a selective GABAA partial agonist being developed

through the U.S. FDA specifically for the treatment of stuttering. In an 8-week, multicenter, double-blind, placebo-controlled study of 132 patients aged 18e65 years, Maguire et al found that treatment with pagoclone (0.15e0.30 mg, given twice daily) resulted in a 19.4% reduction in percentage of syllables stuttered, with a 40% reduction after a subsequent 1-year open-label treatment. Furthermore, Pagoclone is well tolerated by patients in the study. The most commonly reported side effect, headache, was reported in 12.5% of treated patients. Nearly 90% of patients electively chose to continue taking the medication during the 1-year, open-label extension portion of the study. Furthermore, patients in the treat-ment group reported a greater sense of control over their stuttering and verbalfluidity without an effect in the reported naturalness of speech. Patients also reported reduced social anxiety, likely due to the medication’s effect on GABA, an anxiety neurochemical, which is not readily observed with the dopamine-blocking agents. The exact mechanism of GABAApartial agonism benefitting speech is

unclear, but may be related to dopamine/GABA interactions in the basal ganglia. In light of its favorable tolerability profile, as well as consistency of effects across multiple efficacy variables, pagoclone may have potential as a pharmacological treatment of stuttering.15 7. Conclusions

Stuttering involves abnormalities influency as well as anxiety and cognitive avoidance. In addition to considering the upcoming revision to the DSM criteria, comprehensive treatment should address all aspects of this disorder, including not only thefluency enhancement, but also improvement of social avoidance, anxiety, and cognitive restructuring. The optimal treatment of stuttering involves a multidisciplinary approach.61

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We suggest that all children, at the age of onset, should be evaluated by a qualified speech-language pathologist. In patients 2e8 years of age, the primary treatment modality should be speech therapy, with possible workup of PANDAS22 in relevant clinical cases. At 8e12 years of age, speech therapy should be continued and further research on the potential risks and benefits of pharmacological treatment in this age group are warranted. At the time this review was written, no pharmacological agent has been approved by the U.S. FDA specifically for the treatment of stuttering.

From adolescence through to adulthood, speech therapy utilizing behavioral62 and cognitive methods63 should be continued, and a trial of medications is warranted. Stuttering onset after 9 years of age should be worked up for possible“acquired” causes. An adequate trial of medication is at least 3 months, as studies have suggested that the medication needs to be continued to maintain its efficacy.

We further suggest that a physician should collaborate with a speech-language pathologist to help assess the patient’s progress in treatment and to assist the patient through speech therapy. A clinician should enquire as to the patient’s fluency of speech during different social situations (i.e., at work, during introductions, speaking in front of audience, with family) as the level of stuttering can vary depending on the particular speaking environment. The clinician should also be aware that stuttering waxes and wanes over time and should expect to see some“dips” in efficacy during the course of therapy. A longitudinal assessment over a period of months is needed to determine if the stuttering treatment is ef fi-cacious. Additionally, stuttering treatment should also address the level of social and cognitive avoidance that often accompanies this disorder.64

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(6)

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數據

Table 2 DSM-5 proposed revision of diagnostic criteria for childhood onset fluency disorder (stuttering)

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