Stereotypies are defined broadly as repetitive, purposeless movements that are not oscillatory enough to be considered a tremor. Probably the most common etiology of stereotype is tardive dyskinesia (TD). Other common causes of stereotypies include restless legs syndrome, pervasive developmental disorder, and possibly akathisia. The actual phenomenology of stereotype in these disparate conditions varies widely, and the sensory component to the movements ranges from none, in most cases of TD, to severe, in cases of akathisia. They also range from very simple movements to complex, well formed movements.
There are other abnormal movements, not considered to be stereotype, that range on a spectrum of controllability. Tics are repetitive, patterned movements out of a normal background. Usually, there is an urge or premonitory sensation.1 They are usually suppressible, and often suggestible. Compulsions are usually more complex acts in response to some obsessive need to perform the act. Punding is another term for repetitive, complex, reward-seeking behaviors that are associated with Parkinson’s disease and amphetamine/cocaine use, but can be considered a compulsion.2 Although these conditions are associated with particular diseases, they overlap clinically, and cannot be entirely segregated on the basis of strict definitions. In our opinion, there is a spectrum from truly involuntary movements, such as chorea, to movements associated with a simple urge (many stereotypies and tics), to complex actions in response to anxiety (compulsions).
Frontotemporal dementia (FTD) is an umbrella term for a clinically, pathologically, and genetically heterogeneous group of neurodegenerative conditions that predominately affect the frontal and temporal lobes, and lack Alzheimer’s or Lewy-body pathology.3 Series suggest that between 40% and 80% of cases of FTD have some “stereotype” or “compulsion,” terms, which descriptively overlap in different reports.4–9
We describe seven cases of severe stereotype associated with dementia most consistent with FTD, which improved dramatically with tetrabenazine (TBZ), and discuss the implications for pathophysiology based on this finding
This right-handed, retired nursing assistant presented with personality changes at age 61. Shortly thereafter, she developed tongue protrusion, accompanied by the complaint that something was stuck in her mouth. Over the next 2 years, mental status fluctuated, with episodes of disorientation and agitation. Multiple evaluations for acute mental-status changes were unrevealing. She refused to eat and became very withdrawn. By age 63, she resided in a nursing home and had a PEG tube. Trihexyphenidyl mildly improved the movements. Subsequent trials of several dopamine antagonists, long after the onset of movements, as well as citalopram, and valproate, were not helpful.
At our evaluation, her Montreal Cognitive Assessment (MoCA) was 3/30; she had mild spasticity, could not stand or ambulate, but did not have clear parkinsonism (bradykinesia or rigidity). There was almost no verbal output, but she had relatively preserved praxis and could follow simple commands. She demonstrated intermittent tongue protrusion, jerky bilateral hand tremor, bradykinesia; stooped posture; and a slow, wide-based gait.
TBZ was titrated to 25 mg 3×/day, and valproic acid was discontinued. Subsequently, the tongue movements completely stopped, and, surprisingly, the gait improved, possibly secondary to stopping valproate. No adverse events were reported with TBZ on stable doses over 6 months.
This 70-year-old, right-handed, white man previously diagnosed with FTD, was referred to our clinic for a 6-month history of repetitive movements. The patient’s initial symptoms began approximately 4 years earlier, with personality change, loss of interest in his usual activities, social withdrawal, and uncharacteristic angry outbursts. Overall, memory and language were relatively intact, and he never had true hallucinations or delusions. He went on several antidepressants and eventually started risperidone approximately 2 years before our evaluation. This resulted in sedation, but did improve some of the impulsivity.
Six months before our evaluation, the patient began to have compulsive repetitive scratching of his head and neck, and legs, to a lesser extent. He denied any itching sensation, but reported an urge to do it. The scratching temporarily relieved this sensation. He could suppress the urge to scratch but it would “build up,” resulting in an overwhelming need to do it. He said that it worsened while sitting or standing and somewhat improved when lying down. His only other involuntary movement was a more recent onset of repetitive throat-clearing noises. He denied any other complex obsessive or compulsive behaviors.
Two months before our evaluation, his medication was changed from risperidone to quetiapine and alprazolam without remission of his compulsive scratching. Other medications at the time of our evaluation included clonidine at night, atomoxetine, and omeprazole.
Formal neuropsychological testing was consistent with FTD, with marked impulsivity, modest problems in visuospatial construction, verbal fluency, executive function, and information-processing speed, without language problems or depressive symptoms. Cranial-nerve examination, motor examination, sensory examination, and reflexes were normal. His gait was stooped but otherwise normal. He nearly-constantly scratched the back of his head, fist, face, chin, neck, and legs, and cleared his throat. This was partially suppressible but associated with increased anxiety when he attempted suppression. He also had a mild action tremor bilaterally.
The patient was diagnosed with stereotypies/tics associated with FTD. A tardive syndrome was thought to be much less likely, given the phenomenology. He was tapered off quetiapine and began on TBZ, which was titrated up to 25 mg tid. He had a dramatic response, with a near-100% improvement in the movements for approximately a year; however, after that, the patient began to have parkinsonian symptoms and signs. The TBZ was reduced to 25 mg twice per day, with reasonably good control but some recrudescence of stereotype. After 2 more years, it was stopped for a short time secondary to the parkinsonism, and the patient had an immediate return of the same symptoms. TBZ was then reinstituted for a subsequent 2 years, with very good control.
The patient is a 58-year-old, right-handed man, who was referred to our clinic for involuntary, repetitive movements. His past medical history was significant for a distant history of Grave’s disease status post-radioactive iodine ablation. Four years before his evaluation here, the family reported changes in personality. He became both more anxious and more apathetic. He later developed stooped posture, drooling, and moderate dysphagia. He has also had a marked worsening in speech, to the point of mutism, and now communicates most effectively using a computer-based keyboard device. The patient also has had some worsening of gait over the past year, including several backward falls. Evaluation included a normal MRI and video EEG monitoring. An electromyogram showed mild sensory neuropathy. Evaluation of his vocal cords had been unrevealing. The patient tried several antiparkinsonian medications without clear benefit. His medications at time of evaluation were levodopa 25/100 qid, thyroid replacement, glycopyrrolate, and warfarin.
Repetitive movements began indolently about 3 years ago, and became severe over the past year. The patient’s main repetitive movement is blotting saliva from his lips. He will do this for hours continuously with his right hand, even if there is no saliva there. He will also repetitively change settings on the TV remote whether or not the television is on, typically pushing a button approximately every 6 to 10 seconds. Less frequently, he taps his fingers and toes.
His mental status exam was difficult to assess because of his mutism, but typed language was fairly preserved. There was no clear apraxia or memory deficit. Cranial-nerve examination demonstrated mild decreased velocity during vertical OKN testing but was otherwise normal. Motor examination demonstrated modest rigidity in the neck but was normal in the arms and legs with regard to strength, tone, and bulk. He did have mild postural instability and displayed pivotal turns but normal stride length.
The patient was diagnosed with probable FTD. Since the stereotypic movements were the major complaint, he was placed on TBZ, which was titrated up to only 12.5 mg tid. He reported complete cessation of facial-blotting movements, button-pushing, and finger and toe movements. At this point, he has had no worsening of motor symptoms or other adverse events after 12 months.
The patient showed a concurrent onset of slowness, gait instability, and social withdrawal/personality changes at age 59. Within 1-to-2 years, he developed marked language dysfunction (expressive more than receptive), and, by age 62, was mute and only able to follow simple commands. He is incontinent but lacks other autonomic symptoms.
From the onset of symptoms, he demonstrated several different stereotypic movements. He compulsively began to touch objects and other people. Over several years, this lessened, but he began to constantly touch his head. More problematically, he constantly picked at his skin, resulting in numerous lesions and infections. An MRI showed nonspecific, moderate atrophy, more evident in the frontal lobe. Evaluation for reversible dementias was unrevealing. Commercially-available gene testing for Progranulin and MAPT did not show known mutations. There was no response to acetylcholinesterase inhibitors or memantine. His bradykinesia symptoms (mostly gait) modestly improved with L-dopa without the development of dyskinesia, hallucinations, or change in stereotype. Several attempts to reduce or stop L-dopa increased bradykinesia without improving the stereotypies. In the past, he was on paroxetine and fluoxetine for “depression” associated with the dementia, without any effect on the stereotypies. TBZ was started after several years in our clinic and titrated to 75 mg/day. The family reported complete cessation in skin-picking and a >90% improvement in head-touching. A 1-month hiatus in treatment due to logistic difficulties in obtaining TBZ resulted in immediate recrudescence to baseline. After restarting at the full dose, the stereotypies stopped within 24 hours. At 16 months, the benefit is unchanged. There was no change in parkinsonism, but TBZ does cause modest sedation.
The patient is a 75-year-old, right-handed woman referred for throat-clearing vocalizations. The patient had first demonstrated cognitive impairment and personality changes approximately 2 years before this, and was diagnosed with dementia. A previous MRI showed fairly extensive periventricular white-matter changes and a small, left-occipital stroke. An EEG demonstrated borderline mild slowing, but no epileptic activity. Formal neuropsychiatric evaluation revealed moderate global deficits, with marked deficits in executive function and visuoconstruction.
Approximately 1.5 years ago, the patient reported that she had a “sinus drip,” which resulted in the need to clear her throat. This began insidiously over a few months, but, during the last year, has been constant and severely disabling. The patient fixated on this, and, in fact, it now dominated her life. She has had extensive otolaryngology evaluations that were unrevealing and attempted several antihistamine and expectorant medications without benefit. She denies any different movements, obsessions, or compulsions. She can suppress this for a brief time, but reports that the urge to clear her throat intensifies.
The patient’s MoCA was 19/30. Her cranial nerves were normal except for occasional saccadic intrusion during smooth pursuit. There were no bulbar abnormalities on examination. Motor examination, sensory examination, gait, and reflexes were unrevealing except for a very mild intermittent rest tremor in the right hand and mild postural and kinetic tremors in the bilateral upper extremities, without myoclonus or dystonia. The throat-clearing was almost constant. There was some degree of suggestibility, and it was somewhat less frequent when the patient was engaged in other cognitive activities. Medications at the time of our visit included galantamine, citalopram, diltiazem, aspirin, estradiol, thyroid replacement, multivitamins, and memantine.
TBZ was titrated to a dose of 25 mg tid, at which she had complete resolution of the throat-clearing. However, this was complicated by sedation and probable parkinsonism, reported by telephone interview. The dose was decreased and increased several times, and, at 4 months after initial evaluation, the patient was on 12.5 mg tid. With this, they reported an approximately 75% improvement in throat-clearing, and mild-to-modest sedation, but no motor changes. On examination, there was no parkinsonism and a marked reduction in throat-clearing.
A 64-year-old, right-handed woman presented with personality changes, dementia, and facial movements. At 61, she developed social withdrawal, tempered by angry outbursts. She would frequently hide in her closet. Approximately 1 year later, she developed persistent tongue and mouth movements associated with a feeling that something was “stuck in my throat.” Speech became strained, and, within a year, she was nearly mute. Overall cognition and motor function rapidly declined.
At our visit, she was mute, with intermittent tongue stereotypies (mostly protrusion), and she had a PEG placed. She was rigid and spastic, with bilateral leg and knee contractures (no asymmetry) and was unable to stand. Her MoCA was 3/30. She had had an extensive evaluation and several admissions for reversible dementias and, neuromuscular disease. MRI (generalized volume loss), lumbar puncture, EEG, SPECT and serologies were unrevealing. No genetic assessments were done. After the onset of movements she tried many medications for these and her psychiatric symptoms. The family felt that trihexyphenidyl helped the facial movements somewhat but an increased dose resulted in “an allergic reaction” necessitating dose reduction. Valproate, haloperidol, risperidone, clonazepam, and citalopram did not affect the movements.
We initiated TBZ and titrated to 25 mg tid. At 2 months, she had a marked reduction in the mouth movements, without adverse events, but there was no other benefit. After 2 additional months it was decided that the overall benefit in her stereotype did not justify the medication cost, and it was withdrawn. The mouth movements returned immediately.
This 66-year-old, retired male chemical engineer began experiencing involuntary movements, misdiagnosed as tremor, at age 60. Over the next few years, he developed marked personality changes, becoming withdrawn and apathetic toward most, but abruptly angry and physically threatening to his spouse and, occasionally, others. He also developed compulsions about what types of food he can eat and exactly how to cut the food. He also developed moderate parkinsonism, which was worse on the right (decreased dexterity and gait/balance) and was diagnosed before our visit as “atypical parkinsonism.” Donepezil, sertraline, and L-dopa had been tried with no subjective benefit in motor of cognitive symptoms. MRI showed modest frontal lobe atrophy. Progranulin and MAPT genes were negative for known FTD mutations.
On examination, his MoCA was good, at 29/30. Affect was withdrawn, with little spontaneous interaction. There was modest symmetric rigidity and bradykinesia. His gait was slow, with a reduced stride length, end-block turns, and retropulsion. Reflexes were diffusely brisk, with bilateral upgoing toes and multiple frontal-release signs. He displayed almost constant finger-rubbing of his right thumb and index finger and bilateral dorsi- and plantar flexion of both feet. Less commonly, he rubbed both hands together.
We first discontinued L-dopa, without subjective change in his parkinsonian symptoms. TBZ was added and titrated to 75 mg/day. At that dose for about 3 months, a “75%” improvement in the movements was reported, but it was felt that balance might be worse. There was no clear change in any other feature. The medication was discontinued with immediate return of the stereotype but no change in balance. At follow-up 3 months later, it was decided that improvement in the stereotype did not justify the cost of the medication.
We report seven cases of stereotype in patients with cognitive changes and either marked personality changes, or mutism/aphasia, whose stereotype were all dramatically improved with TBZ (see Table 1). Although no case was confirmed by genetic analysis or brain pathology, we feel all cases are most consistent with FTD. To our knowledge, this is the first reported treatment of stereotype in FTD other than antidepressants that seems to modestly improve the symptoms.8,10,11 Dopamine antagonists may help stereotype associated with pervasive developmental disorders. All of our patients took antidepressants at some point without subjective benefit in stereotype. As would be expected by a referral to a movement-disorder center, the movements were relatively severe and constituted a major subjective complaint despite other problems. All seven patients had discrete movements and some urge to move, and three could partially suppress the movements, which is also fairly consistent with the definition of a complex motor tic.
TABLE 1.Clinical and Outcome Summary of Cases
| Add to My POL
|Patient||Age at Onset, years||Initial Symptom||Main Cognitive Issues||Anatomy of Stereotype||Parkinsonism Features||TBZ Dose, mg||Percent Improvement at That Dose||Adverse Events|
|1||61||Personality change||Mute||Tongue protrusion||Gait/balance||75||100||None|
|2||65||Personality change||Withdrawn, angry outbursts||Scratching, grunting||None||75 (50)||100 (75)||Parkinsonism|
|3||54||Personality change||Mute; apathy||Hand (blotting, buttons), toes||Gait instability||37.5||100||None|
|4||59||Personality changes, gait||Mute, withdrawn; executive dysfunction||Hands (touching and picking)||None||75||95||Sedation|
|5||73||Personality changes||Obsessions, executive dysfunction||Throat||None||75 (37.5)||100 (75)||Sedation, possible parkinsonism|
|6a||61||Personality changes||Withdrawn, mute||Mouth, face||Gait||75||80||None|
|7a||61||Stereotype||Withdrawn, impulsive; compulsions||Hand, feet||Gait, bradykinesia, rigidity||75||75||Possible worse gait|
Using volumetric MRI, Josephs et al. reported that FTD patients with “stereotype” had a relatively greater loss of striatal gray matter. Rosso et al.7 also reported a tendency for patients with “simple compulsions” to have greater striatal atrophy. Using SPECT, McMurtray et al.12 found relatively greater hypoperfusion in the right frontal lobe in “simple stereotype” and greater left-temporal hypoperfusion for “compulsions.”12 However, specific genetic, histopathologic, and clinical correlations for stereotype in FTD are not established.4
TBZ is a vesicular monoamine type-2 inhibitor that blocks the incorporation and storage of monoamines in their presynaptic vesicles, resulting in increased cytoplasmic metabolism, and thus reduced release of dopamine and histamine, and to a lesser extent norepinephrine and serotonin.13 The improvement seen with TBZ in these cases does not help differentiate tic from stereotype, as it can treat both tardive stereotype14 and tics.15,16 It is not effective for stereotype from acute akathisia or restless leg syndrome.
The dramatic benefit from TBZ suggests that relatively increased dopaminergic, or possibly histaminergic, adrenergic, or serotonergic activity, causes stereotype in FTD. Most basic-science research implicates dopaminergic mechanisms in stereotype;17,18 many diseases associated with stereotype and tics have dopaminergic substrates, and stereotype can be induced with amphetamines and cocaine,2 both of which increase dopaminergic tone. Furthermore, the impulse-control symptoms typical of FTD are similar to those in Huntington’s disease, which is often treated with TBZ, and not inconsistent with impulse-control disorders from dopaminergic-agonist medications when used for Parkinson’s disease.19 TBZ anecdotally improves impulse-control problems in Huntington’s disease, but formal trials for this indication are lacking.
This is a small, open-label report, and must be interpreted with caution. There is no scale for this type of stereotype, so we used percent-improvement and global impressions. The stereotype markedly improved in all cases, but the impact of this on overall quality of life in this population is not clear, as there was usually no overt benefit in other features of their illness. Although fairly well tolerated in this group, TBZ has also been associated with depression and carries a black box warning for suicide. More commonly, it can cause parkinsonism, sedation, and insomnia. Parkinsonism is often reported in series of FTD cases, but more detailed descriptions (amounts of bradykinesia, rigidity, rest tremor, gait/balance disorder, symmetry, L-dopa responsiveness, etc.) are lacking. Our patients with parkinsonism most commonly had gait/balance disorders at baseline, which were possibly exacerbated in one case after TBZ. Most generally lacked hypokinesia, tremor, and rigidity, and were not L-dopa responsive.
We feel that TBZ could be clinically considered in cases where stereotype is problematic, and that further studies are justified, especially a more detailed assessment of behavioral outcomes. The dramatic benefit also raises interesting questions about pathophysiologic mechanisms, especially why monoamine depletion would dramatically benefit a feature of this neurodegenerative disorder.
Dr. Ondo receives speaking fees from Lundbeck, TEVA, GSK, Allergan, Ipsen, Merz, and Novartis, and is a speaker and consultant for GSK, BI, TEVA, Allergan, Ipsen, and Lundbeck.
Grant support from Parkinson Study Group, Huntington’s Study Group, Ipsen, Allergan, Novartis, TEVA, Takeda