Tic disorders

Tic disorders are a clinical spectrum that ranges from mild, sporadic tics to Tourette's syndrome (Tourette's disorder).[2][12][13] Tic disorders can be either primary or secondary to an underlying condition.[1][14] Most tic disorders are primary, with the onset almost always being in childhood or adolescence. Primary tics can be idiopathic or inherited:

Primary tics

'Transient tics'/provisional motor or vocal tics (<1 year)

Persistent (chronic) motor or vocal tics (>1 year)

Tourette's syndrome (idiopathic or inherited)

Tic disorder without an identifiable cause (e.g., with tic onset in a person over age 18 years).

Secondary tics can be due to:

Infections (e.g., encephalitis, Creutzfeldt-Jakob disease, and Sydenham's chorea). There is conflicting evidence concerning an association between tics and recurrent group A streptococcal infections.[15]
Substance abuse (stimulant abuse being the most common)
Medicine (e.g., lamotrigine)[16]
Toxins (e.g., carbon monoxide)
Head trauma
Stroke
Metabolic and endocrine (chorea gravidarum, thyrotoxicosis)
Neurodegenerative (Huntington’s disease, Wilson’s disease, neuroacanthocytosis, neurodegeneration with brain iron accumulation).

It is hypothesised that tic disorders result from a disturbance in the basal ganglia, leading to disinhibition of the motor and limbic systems. This hypothesis is supported by multiple neuroimaging and animal studies, which suggest that the pathophysiology of Tourette's syndrome (Tourette's disorder) involves projections of the primary motor, secondary motor, and somatosensory cortex to the basal ganglia.[17][18] Preclinical research in mouse models has shown evidence for microglial dysregulation in Tourette's syndrome.[19]

Tic form appears determined by the location of focal disinhibition within the somatotopic organisation of the striatum, whereas cortical activation appears to determine the timing of individual tics.[20] In adults with Tourette's syndrome, structural abnormalities have been observed in cortico-striato-pallido-thalamic white matter pathways. Furthermore, abnormalities in cortico-striatal, thalamo-cortical, and thalamo-putaminal pathways were positively correlated with tic severity.[21][22] Several magnetic resonance imaging (MRI) volumetric studies found that patients with severe tics often have thinning of the sensorimotor cortices and reduced caudate volumes.[23] MRI findings in children with Tourette's syndrome include lower white matter volume bilaterally in the orbital and medial prefrontal cortex, and greater grey matter volume in the posterior thalamus, hypothalamus, and midbrain.[24] Functional MRI data suggest that the relationship between aberrant subcortical afferents to the primary motor cortex and inputs from the premotor cortex may be implicated in disease severity.[25]

Dysfunction of the cortico-striato-thalamo-cortical circuitry in Tourette's syndrome appears to involve an array of different neurotransmitters including dopamine, noradrenaline (norepinephrine), serotonin, histamine, gamma-aminobutyric acid, glutamine, acetylcholine, and others.[26][27][28]

Tic disorders are frequently present in multiple family members, indicating a genetic basis for these disorders. However, there have been conflicting data regarding the roles of some genes previously implicated in tic disorders. A study on 465 probands with chronic tic disorder (93% Tourette's syndrome) and both parents from 412 families, as well as some proband siblings, found no evidence for involvement of DRD2, HDC, MAO-A, SLC6A3/DAT1, TPH2, COMT, GABRA2, SLC1A1, and HRH3, which were previously implicated neurotransmitter-related candidate genes. Additionally, the study did not provide support for involvement of single nucleotide polymorphisms (SNPs) previously implicated in candidate genes BTBD9, CNTNAP2, DLGAP3, SLITRK1, and TBCD; top SNPs from genome-wide association studies on Tourette's syndrome and related disorders; the top five linkage disequilibrium-independent SNPs from the first genome-wide association study of Tourette's syndrome; or the SLITRK1 candidate gene.[29]

Many researchers feel that Tourette's syndrome likely does not have a monogenic Mendelian pattern of inheritance, but rather results from the interplay of multiple genes. There is increasing evidence that the genetics of Tourette's syndrome is complex and may overlap with other psychiatric disorders such as obsessive-compulsive disorder (OCD) and ADHD.[30] Research is also focusing on potential epigenetic factors that impact on gene expression. Altered epigenetic regulation of dopaminergic genes appears to play a role in the pathophysiology of Tourette's syndrome. It is suggested that tic fluctuations may occur as a result of short-term alterations of methylation levels of dopaminergic genes, which in turn affects tonic and phasic dopaminergic signalling in the striatum and thalamo-cortical output pathways.[31]

Immunological mechanisms have also been hypothesised to play a role in the pathophysiology of tic disorders. Maternal history of autoimmune disease was linked to a higher incidence rate of Tourette's syndrome among offspring, especially among male offspring.[32][33] Personal immunological factors may also be involved. Group A streptococcal exposure or infection has been linked to tic disorders and OCD.[34][35] This disorder characterised by tic disorders or OCD is termed paediatric auto-immune neuropsychiatric disorders associated with streptococcal infections (PANDAS).[15] The PANDAS criterion has been modified to eliminate the specific aetiological factors (i.e., streptococcal infection) and focus on the initial presentation of symptoms. This expanded clinical entity is termed paediatric acute-onset neuropsychiatric syndrome (PANS) due to increasing evidence showing that rapid changes in personality are not just linked to streptococcal infections but may include many physiological stressors, such as influenza.[36] The term 'childhood acute neuropsychiatric symptoms' (CANS) is also used to describe this phenotype, typically by neurologists, but has a broader diagnostic scope, including children and adolescents with acute onset of symptoms associated with infectious, post-infectious, drug-induced, auto-immune, metabolic, traumatic, psychogenic, and other factors. Furthermore, tics have now been removed from the primary diagnostic criteria for PANS/CANS.[36][37]

Clinical classification[1][3]

Simple motor tics

Grimacing
Blinking
Head jerking
Shoulder shrugging
Abdominal tensing
Kicking.

Simple vocal tics

Sniffing
Grunting
Throat clearing
Barking
Snorting
Coughing.

Complex motor tics

Head shaking
Skipping
Hopping
Finger cracking
Touching
Jumping
Rubbing
Echopraxia (imitating other people's gestures)
Copropraxia (performing obscene gestures).

Complex vocal tics

Whistling
Speech irregularities including changes in pitch or volume
Belching
Unintelligible or nonsensical words or phrases
Coprolalia (uttering obscenities or profanities)
Echolalia (repeating other people's words or phrases)
Palilalia (repeating one's own words, particularly the last syllable).

Pathophysiology

Classification

Clinical classification[1][3]