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      Streptococcal Infection as a Major Historical Cause of Stuttering: Data, Mechanisms, and Current Importance

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          Abstract

          Stuttering is one of the most well-known speech disorders, but the underlying neurological mechanisms are debated. In addition to genetic factors, there are also major non-genetic contributions. It is here proposed that infection with group A beta-hemolytic streptococcus (GAS) was a major underlying cause of stuttering until the mid-1900s when penicillin was introduced in 1943. The main mechanism proposed is an autoimmune reaction from tonsillitis, targeting specific molecules, for example within the basal ganglia. It is here also proposed that GAS infections may have continued to cause stuttering to some extent, to the present date, though more rarely. If so, early diagnosis of such cases would be of importance. Childhood cases with sudden onset of stuttering after throat infection may be particularly important to assess for possible GAS infection. The support for this hypothesis primarily comes from three lines of argument. First, medical record data from the 1930s strongly indicates that there was one type of medical event in particular that preceded the onset of childhood stuttering with unexpected frequency: diseases related to GAS throat infections. In particular, this included tonsillitis and scarlet fever, but also rheumatic fever. Rheumatic fever is a childhood autoimmune sequela of GAS infection, which was a relatively widespread medical problem until the early 1960s. Second, available reports of changes of the childhood prevalence of stuttering indicate striking parallels between stuttering and the incidence of rheumatic fever, with: (1) decline from the early 1900s; (2) marked decline from the introduction of penicillin in the mid 1940s; and (3) reaching a more stable level in the 1960s. The correlations between the data for stuttering and rheumatic fever after the introduction of penicillin are very high, at about 0.95. Third, there are established biological mechanisms linking GAS tonsillitis to immunological effects on the brain. Also, a small number of more recent case reports have provided further support for the hypothesis linking stuttering to GAS infection. Overall, it is proposed that the available data provides strong evidence for the hypothesis that GAS infection was a major cause of stuttering until the mid-1900s, interacting with genetic predisposition.

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          The global burden of group A streptococcal diseases.

          The global burden of disease caused by group A streptococcus (GAS) is not known. We review recent population-based data to estimate the burden of GAS diseases and highlight deficiencies in the available data. We estimate that there are at least 517,000 deaths each year due to severe GAS diseases (eg, acute rheumatic fever, rheumatic heart disease, post-streptococcal glomerulonephritis, and invasive infections). The prevalence of severe GAS disease is at least 18.1 million cases, with 1.78 million new cases each year. The greatest burden is due to rheumatic heart disease, with a prevalence of at least 15.6 million cases, with 282,000 new cases and 233,000 deaths each year. The burden of invasive GAS diseases is unexpectedly high, with at least 663,000 new cases and 163,000 deaths each year. In addition, there are more than 111 million prevalent cases of GAS pyoderma, and over 616 million incident cases per year of GAS pharyngitis. Epidemiological data from developing countries for most diseases is poor. On a global scale, GAS is an important cause of morbidity and mortality. These data emphasise the need to reinforce current control strategies, develop new primary prevention strategies, and collect better data from developing countries.
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            Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases.

            The purpose of this study was to describe the clinical characteristics of a novel group of patients with obsessive-compulsive disorder (OCD) and tic disorders, designated as pediatric autoimmune neuropsychiatric disorders associated with streptococcal (group A beta-hemolytic streptococcal [GABHS]) infections (PANDAS). The authors conducted a systematic clinical evaluation of 50 children who met all of the following five working diagnostic criteria: presence of OCD and/or a tic disorder, prepubertal symptom onset, episodic course of symptom severity, association with GABHS infections, and association with neurological abnormalities. The children's symptom onset was acute and dramatic, typically triggered by GABHS infections at a very early age (mean = 6.3 years, SD = 2.7, for tics; mean = 7.4 years, SD = 2.7, for OCD). The PANDAS clinical course was characterized by a relapsing-remitting symptom pattern with significant psychiatric comorbidity accompanying the exacerbations; emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, oppositional behaviors, and motoric hyperactivity were particularly common. Symptom onset was triggered by GABHS infection for 22 (44%) of the children and by pharyngitis (no throat culture obtained) for 14 others (28%). Among the 50 children; there were 144 separate episodes of symptom exacerbation; 45 (31%) were associated with documented GABHS infection, 60 (42%) with symptoms of pharyngitis or upper respiratory infection (no throat culture obtained), and six (4%) with GABHS exposure. The working diagnostic criteria appear to accurately characterize a homogeneous patient group in which symptom exacerbations are triggered by GABHS infections. The identification of such a subgroup will allow for testing of models of pathogenesis, as well as the development of novel treatment and prevention strategies.
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              Stuttering and the basal ganglia circuits: a critical review of possible relations.

              Per Alm (2004)
              The possible relation between stuttering and the basal ganglia is discussed. Important clues to the pathophysiology of stuttering are given by conditions known to alleviate dysfluency, like the rhythm effect, chorus speech, and singing. Information regarding pharmacologic trials, lesion studies, brain imaging, genetics, and developmental changes of the nervous system is reviewed. The symptoms of stuttering are compared with basal ganglia motor disorders like Parkinson's disease and dystonia. It is proposed that the basal ganglia-thalamocortical motor circuits through the putamen are likely to play a key role in stuttering. The core dysfunction in stuttering is suggested to be impaired ability of the basal ganglia to produce timing cues for the initiation of the next motor segment in speech. Similarities between stuttering and dystonia are indicated, and possible relations to the dopamine system are discussed, as well as the interaction between the cerebral cortex and the basal ganglia. Behavioral and pharmacologic information suggests the existence of subtypes of stuttering. As a result of this activity, the reader will (1) become familiar with the research regarding the basal ganglia system relating to speech motor control; (2) become familiar with the research on stuttering with indications of basal ganglia involvement; and (3) be able to discuss basal ganglia mechanisms with relevance for theory of stuttering.
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                Author and article information

                Contributors
                Journal
                Front Hum Neurosci
                Front Hum Neurosci
                Front. Hum. Neurosci.
                Frontiers in Human Neuroscience
                Frontiers Media S.A.
                1662-5161
                09 November 2020
                2020
                : 14
                : 569519
                Affiliations
                Department of Neuroscience, Uppsala University , Uppsala, Sweden
                Author notes

                Edited by: Pierpaolo Busan, San Camillo Hospital (IRCCS), Italy

                Reviewed by: Tim Saltuklaroglu, The University of Tennessee, Knoxville, United States; Gerald Maguire, University of California, Riverside, United States

                *Correspondence: Per A. Alm per.alm@ 123456neuro.uu.se

                Specialty section: This article was submitted to Speech and Language, a section of the journal Frontiers in Human Neuroscience

                Article
                10.3389/fnhum.2020.569519
                7693426
                33304252
                96e4e2aa-99a2-430a-8da7-6e890f0801ce
                Copyright © 2020 Alm.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 June 2020
                : 24 August 2020
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 102, Pages: 20, Words: 116323
                Funding
                Funded by: Uppsala Universitet 10.13039/501100007051
                Funded by: Region Uppsala 10.13039/501100014688
                Categories
                Human Neuroscience
                Hypothesis and Theory

                Neurosciences
                stuttering,infection,group a beta-hemolytic streptococci,streptococcus pyogenes,autoimmunity,inflammation,epidemiology,basal ganglia

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