Multiple system atrophy (MSA) is a heterogenous condition, presenting with core clinical features of autonomic dysfunction, parkinsonism, and/or cerebellar ataxia. The presence of alpha-synuclein glial cytoplasmic inclusion is the hallmark of MSA. It shares a common pathological origin with Parkinson's disease (PD) and Lewy body dementia (DLB) and they are collectively grouped as "synucleinopathies." The pathological synuclein protein is now well- recognized in skin biopsies of these patients. Besides the pathological findings, radiological investigation is a useful diagnostic tool. Brain MRI helps rule out other etiologies, and findings like the "Hot-cross bun" sign, "putaminal atrophy," and "infratentorial findings" can assist with the diagnosis of MSA. Cardiac MIBG scan, autonomic testing, urodynamic studies can help differentiate MSA from other conditions. Although diagnostic tools are available for MSA diagnosis, clarity is needed on when to use these tests. We suggest a diagnostic algorithm to navigate the use of these tests. However, this algorithm is not intended to replace the use of current MDS diagnostic criteria of MSA.

We propose the use of the term tardive dyskinesia to refer to the original description of repetitive and complex oral-buccal-lingual (OBL) movements and the analogous repetitive movements of the limbs, trunk, or pelvis. The term tardive syndrome is an umbrella term to be used to refer to the spectrum of all persistent hyperkinetic, hypokinetic, and sensory phenomenologies resulting from chronic dopamine receptor blocking agent (DRBA) exposure. TD is a type of TS. The term tardive dystonia (TDyst) should be used when dystonia is the main feature of TS. Retrocollis and oromandibular dystonia appear to be the most common form of Tdyst. Tardive akathisia refers to the inability to remain still with an urge to move, giving the appearance of restlessness. In tardive tourettism, the patient has complex motor and phonic tics associated with premonitory urge and relief of tension after performing the tic behavior, thus resembling Tourette's syndrome. Tardive tremor is composed of mainly postural and kinetic tremors. It differs from the resting tremor seen in drug-induced parkinsonism. Tardive pain occurs in association with chronic use of DRBAs and involves the mouth, tongue, and genital region with no physical findings. In tardive parkinsonism, the patient has persistent parkinsonism even after discontinuation of the DRBA although this diagnosis is in question and may represent DRBA-uncovered idiopathic Parkinson's disease or coincident development of Parkinson's disease while taking DRBAs.

Since the original description of side effects of neuroleptics, different terminologies and definitions for tardive dyskinesia (TD) and tardive syndrome (TS) have been used by different authors, and often these two terms have been used interchangeably. This paper proposes a nosology designed to define and clarify various terms and phenomenologies within the TS spectrum. We propose to use the term tardive dyskinesia to refer to the original description of repetitive and complex oral-buccal-lingual (OBL) movements, as well as to the analogous repetitive movements that can appear in the limbs, trunk, or pelvis. The repetitive, relatively rhythmic nature of the movements is the common denominator of this phenomenologic category. The term tardive syndrome refers to the spectrum of all persistent hyperkinetic, hypokinetic and sensory phenomenologies resulting from chronic dopamine receptor blocking agents (DRBA) exposure. Thus, TS is an umbrella term. When dystonia is the main feature of TS it is considered to be tardive dystonia (TDyst). Retrocollis appears to be the predominant form of cervical dystonia in this condition. Cranial dystonias, particularly oromandibular dystonia, are also common forms of TDyst. Tardive akathisia refers to the inability to remain still with an urge to move, giving the appearance of restlessness. It is a sensory phenomenon and a common and disabling form of TS. Unlike acute akathisia, tardive akathisia tends to occur late and persists after the drug is withdrawn. In tardive tourettism, the patient exhibits the features of Tourette syndrome with complex motor and phonic tics associated with premonitory urge and relief of tension after performing the tic behavior. Tardive tremor differs from the resting tremor seen in drug-induced parkinsonism in that it is mainly a postural and kinetic greater than resting tremor. Tardive pain has been reported in association with chronic use of DRBA's. The pain involved the mouth, tongue and the genital region. The patients tended to obsess over the pain and usually had some other form of motor tardive syndrome, either tardive dyskinesia, tardive akathisia or tardive dystonia. The term tardive parkinsonism has been proposed for those drug induced parkinsonism patients who have persistent symptoms following discontinuation of the DRBA. However, there is a strong possibility that the DRBA may have simply unmasked subclinical parkinsonism or that there is coincident Parkinson disease developing during the period the patient is taking the DRBA.

Tardive syndromes (TDS) are a group of hyperkinetic and hypokinetic movement disorders that occurs after exposure to dopamine receptor blocking agents such as antipsychotic and antiemetic drugs. The Abnormal Involuntary Movement Scale (AIMS) is a widely used instrument that has become the standard for assessment of tardive dyskinesia (TDD), the most common form of TDS. However, the AIMS has a number of clinimetric limitations and was designed primarily to assess the anatomic distribution and severity of involuntary movements without regard to phenomenology. To build on recent advances in understanding and treatment of TDS, re-evaluation and revision of the AIMS that could aid both clinical practice and research may be worthwhile. Challenges, such as retaining the efficiency of the current AIMS, incorporating evaluation of impairment in daily activities, and re-training clinicians for a revised examination procedure and rating instrument, are very likely surmountable.

Background

CVT-301 (Inbrija) is a self-administered orally inhaled levodopa approved for the intermittent treatment of OFF episodes in patients with Parkinson's disease (PD) treated with carbidopa/levodopa. Prior studies only evaluated CVT-301 after the first ON of the day.

Objective and methods

The objective of this study was to evaluate the safety and tolerability of CVT-301 for early morning OFF. Using a randomized, double-blind, 2-way crossover design, eligible patients in the morning OFF state (having not received PD medication overnight) received a single dose of CVT-301 84 mg or placebo on 2 dosing days, immediately after their first morning oral carbidopa/levodopa dose. Safety assessments included treatment-emergent adverse events, vital signs, and patient- and examiner-reported dyskinesia. An exploratory efficacy assessment was examiner-rated time-to-ON with carbidopa/levodopa + CVT-301 vs carbidopa/levodopa + placebo.

Results

Of the 36 patients (mean age 62.9 years) who enrolled and completed the study, 9 (25.0%) reported treatment-emergent adverse events following CVT-301 administration; 4 (11.1%) reported treatment-emergent adverse events following placebo. The most common adverse event was cough (4 [11.1%] for CVT-301 vs 1 [2.8%] for placebo), which was typically mild and transient. Incidence of asymptomatic orthostatic hypotension (CVT-301, 6; placebo, 7) and examiner-rated dyskinesia were similar for both (36-39% mild, 3-6% moderate, and 0% severe). Median time-to-ON was 25.0 min following carbidopa/levodopa + CVT-301 and 35.5 min following carbidopa/levodopa + placebo (P = 0.26). At 30 min, more patients had turned ON following carbidopa/levodopa + CVT-301 administration (66.7%), compared with carbidopa/levodopa + placebo (44.5%) (P = 0.040).

Conclusion

Single doses of CVT-301 84 mg administered with oral carbidopa/levodopa for early morning OFF symptoms were well-tolerated, with no notable safety concerns.