A new clinical feature associated with familial early-onset of dystonic-guttural tics: An unusual diagnosis of PANDAS.

Until today there is a large debate about the existence of PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) or PANS (pediatric acute onset neuropsychiatric syndrome). These children usually have dramatic, "overnight" onset of symptoms, including motor or vocal tics, obsessions, and/or compulsions. In addition to these symptoms, children may also have comorbid features of associated disorders. Herein, we report a family with an early onset of tics, with exclusively dystonic and guttural tics. All patients had a particularly strong excitement trigger. Two of the patients were shown to have signs suggestive of PANDAS and all family members were Group A beta-hemolytic Streptococcus (GABHS) carriers. The PANDAS spectrum is probably a group of disorders. We have described a PANDAS variant, in which the family seems to share common autoimmune pattern and may be viewed in the large spectrum of PANDAS.

Introduction

Until today there is a large debate about the existence of PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) or PANS (pediatric acute onset neuropsychiatric syndrome) according to the recent introduction of this title by Swedo et al.[1] The possibility of a causal linkage between Group A beta hemolytic Streptococcus (GABHS) infections and PANDAS/PANS is based: 1 - On the possible similar mechanisms of this syndrome with Sydenham's chorea and 2 - that this last disorder display de novo tics and obsessive-compulsive symptoms as happens with PANDAS/PANS. Murphy et al.,[2] reports that patients diagnosed with PANDAS versus patients without PANDAS were more likely to suffer from dramatic onset, definite remission, and remission of neuropsychiatric symptoms during antibiotic therapy; a history of surgery for adenotonsillectomy evidence of GABHS and clumsiness.

These children usually have dramatic, “overnight” onset of symptoms, including motor or vocal tics, obsessions, and/or compulsions. In addition to these symptoms, children may also have comorbid features of associated disorders attention deficit hyperactivity disorder (ADHD), anorexia, pervasive developmental disorder, dystonia, and restless leg syndrome.[123456]

Here we report a family (four cases over two generations) affected by tic disorders with unusual features, with a chronic history of vocal and motor tics. Unlike Tourette syndrome, tics began in infancy, were stable over time, and had unusual dystonic-guttural features. These features were present in at least four family members on paternal side.

Case Report

A 5-year-old Caucasian male child was admitted at Morristown Memorial Hospital, Morristown, New Jersey, USA, for the persistence of the problem since 1 year of age, when he was first referred to his pediatrician. He was a male, second-born by healthy nonconsanguineous parents. He was born at 40 weeks of gestation by normal delivery after uncomplicated pregnancy.

The parents described the child's movements as very brief, repetitive, mostly involving facial contortion and dystonic type movements of opening of the jaw, extension, and closure of the wrist on one side, and sometimes associated with explosive type breathing movements such as “uh, uh, uh” or occasionally coughing. Episodes were very brief and usually the patient could voluntarily suppress the movements. Moreover, they were very reliably precipitated by events that got the patient excited or nervous. Of note, the movements and vocalization had been similar in nature since their onset in infancy; there have been no other transient movements noted.

His family history was remarkable. The propositus’ sister had similar movements, which began in infancy before the age of 6 months and almost disappeared by the age of 7 years. Movements in his sister could be confirmed by direct observation of videotapes. The patient's father also had similar movements between age 1 and 5, also associated with guttural tics. He had a history of recurrent and recalcitrant streptococcal infections. At the time of our initial exam of the child, the father had recalcitrant GABHS pharyngitis that had failed to improve despite sequential trials of five different antibiotics. Father's mother also had similar movements during the first few years of life and had the lifelong nickname “wood-a wood-a wood-a” due to her guttural tics as a child. She also had acute rheumatic fever in early childhood, after her movements had resolved.

On physical examination, the child was in good health. Examination of head, ears, eyes, nose, and throat (HEENT); chest, abdomen, and extremities were normal.

On neurological examination, at the age of 3 years, the child had very prominent dystonic motor tics, at least one episode per minute, each lasting no more than 2 seconds. He would have episodes of sustained jaw opening, sustained extension of usually his right arm, and sometimes his left associated with clenching of fist on that side and this was sometimes relieved by “ah, uh, ah” type sound or a sound of breathing against a closed glottis. Tics were rather stereotyped in nature. Occasionally, he would have other movements of the face, but these were less prominent dystonic movements. Episodes could very reliably be elicited by getting the child excited; this could be something as simple as talking about his favorite dinosaurs or his favorite superhero.

Formal cranial nerve examination revealed normal visual fields. Extraocular movements were full. Facial movements were symmetric. Darting tongue and milkmaid grip were present bilaterally, but no choreiform movements were present. Motor strength was 5/5 throughout. There was no pronator drift. There was no dystaxia on finger-to-nose or heel-to-shin testing. Gait was performed normally in the standard fashion. He could hop equally well on either foot. His tandem gait was somewhat deficient, but this might have been age-appropriate.

As far as instrumental exams were concerned, electrocardiogram (EKG) and cardiac echocardiography were normal. Magnetic resonance imaging (MRI) and electroencephalogram (EEG) were also normal. In view of the recent association of streptococcal infections and other infections with tics, a limited workup was performed. Lyme and Epstein-Barr virus (EBV; both IgG and IgM) titers were negative. Anti-streptolysin O (ASLO) titer was elevated at 354 IU/ml (normal 0-170) and anti-deoxyribonuclease (DNase) B titers marker elevated at 1:1,360 (normal <1:170). Throat culture was positive for GABHS. The child was treated with 10 days of 12 mg/kg azithromycin with marked improvement of symptoms-episodes ceased following the 3rd day of treatment, and he remained tic-free for the next month. Throat culture following 10 days of treatment was negative. Prophylactic treatment was offered at the outset, but parents refused. One month later, the child developed recrudescence of tics. ASLO and anti-DNase B were again elevated at 425 IU/ml and 1:1,920, respectively, and throat culture was again positive for GABHS. The child was treated with azithromycin as before and again improved.

Discussion

The existence of PANDAS and/or PANS is still largely debated. Schrag et al.,[7] refers not having found a strong relationship between streptococcal infections and neuropsychiatric syndromes such as obsessive-compulsive disorder (OCD) and Tourette syndrome. On the other hand, Leslie et al.,[8] report that subjects with newly diagnosed OCD, tics, or Tourette syndrome were more likely than controls to have had a diagnosis of streptococcal disorders, in the previous year and concluded that some pediatric onset neuropsychiatric disorders including OCD, tic disorders, ADHD, and major depressive disorder may be temporally related to prior streptococcal infections.

We report a patient with the onset of stereotypic dystonic and guttural vocal tics with onset in infancy. Furthermore, these movements are strongly stimulus-elicited and have been qualitatively stable over the period of at least 4 years. The correlation of tic symptoms with GABHS infection suggested that the patient might have a PANDAS variant.

There is a particularly strong genetic component in this family. There are at least four affected family members all through father's side, a very early onset less than age 2, the presence of dystonic and explosive tics, and a strong emotional trigger. The pedigree suggests autosomal dominant inheritance. However, the results of streptococcal testing in the patient and response to antibiotics suggest the possibility of a streptococcal trigger to the movements. Also, there is a history of unusually severe complications of GABHS infection in the patient's father and paternal grandmother. The simplest explanation of these findings is to postulate the presence of an autosomal dominant predisposition to severe GABHS infection and GABHS-associated symptoms, that is, a genetically determined PANDAS variant.

This patient has a history of more than a year of motor and vocal tics and so might be thought to have Tourette syndrome (TS). This is a disorder characterized by simple and complex motor tics, vocal tics, and frequently obsessive-compulsive symptoms. Its onset occurs before the age of 21.[13] Typically, TS shows a waxing and waning course, but a chronification of the tics, even during later life, is often observed. TS mainly occurs in boys, and shows genetic heritability with differing penetrance. The pathological mechanism is still unclear. Neuroanatomical and neuroimaging studies, as well as effective treatment using antipsychotics, suggest that a disturbance of the dopaminergic system in the basal ganglia plays an important role in the pathogenesis of TS.[910] Several possibly causative mechanisms of the disturbed dopaminergic neurotransmission have been proposed, although today the main emphasis is given on the infection-triggered inflammatory immune process. Extrapyramidal movement disorders are known to occur as a symptom of post-streptococcal disease, such as in Sydenham's chorea. Cases of childhood TS are proposed to be caused by such a post-streptococcal mechanism, being part of a spectrum of childhood PANDAS. The overlap between TS and PANDAS is already known, but these family resembling both PANDAS and Tourette syndrome, have some issues that can be recorded as Tourette syndrome and other as PANDAS. For example, the strong genetic component involving both males and females, the very early onset of the disease, the presence of dystonic and explosive tics and a strong emotional trigger, and at the end the prompt response to therapy. In literature, it has also been found that prophylaxis with penicillin and azithromycin were effective in decreasing streptococcal infections and neuropsychiatric symptom exacerbations among children in the PANDAS subgroup.[10]

So far, the PANDAS spectrum is probably a heterogeneous and overlapping group of disorders, with pure “classical” PANDAS being relatively uncommon. Several authors including our group have described PANDAS spectrum, which differ in only minor ways from classical PANDAS.[1236] These variants seem to share common autoimmune features and are probably best viewed as part of a PANDAS spectrum at this time. Some of these variant overlapping one by one, and with other disease especially, with Tourette syndrome.[168] In these variants group, we encountered this family with an early onset (infantile type) and unusual features.[1]