Petra Havránková

The Subthalamic Microlesion Story in Parkinson's Disease: Electrode Insertion-Related Motor Improvement with Relative Cortico-Subcortical Hypoactivation in fMRI

Electrode implantation into the subthalamic nucleus for deep brain stimulation in Parkinsons disease (PD) is associated with a temporary motor improvement occurring prior to neurostimulation. We studied this phenomenon by functional magnetic resonance imaging (fMRI) when considering the Unified Parkinsons Disease Rating Scale (UPDRS-III) and collateral oedema. Twelve patients with PD (age 55.9± (SD)6.8 years, PD duration 9–15 years) underwent bilateral electrode implantation into the subthalamic nucleus. The fMRI was carried out after an overnight withdrawal of levodopa (OFF condition): (i) before and (ii) within three days after surgery in absence of neurostimulation. The motor task involved visually triggered finger tapping. The OFF/UPDRS-III score dropped from 33.8±8.7 before to 23.3±4.8 after the surgery (p<0.001), correlating with the postoperative oedema score (p<0.05). During the motor task, bilateral activation of the thalamus and basal ganglia, motor cortex and insula were preoperatively higher than after surgery (p<0.001). The results became more enhanced after compensation for the oedema and UPDRS-III scores. In addition, the rigidity and axial symptoms score correlated inversely with activation of the putamen and globus pallidus (p<0.0001). One month later, the OFF/UPDRS-III score had returned to the preoperative level (35.8±7.0, p = 0.4). In conclusion, motor improvement induced by insertion of an inactive electrode into the subthalamic nucleus caused an acute microlesion which was at least partially related to the collateral oedema and associated with extensive impact on the motor network. This was postoperatively manifested as lowered movement-related activation at the cortical and subcortical levels and differed from the known effects of neurostimulation or levodopa. The motor system finally adapted to the microlesion within one month as suggested by loss of motor improvement and good efficacy of deep brain stimulation.

DYT 6--a novel THAP1 mutation with excellent effect on pallidal DBS.

DYT6 is an early-onset dystonia caused by variable mutations of the gene encoding the thanatos-associated protein (THAP1).1 It usually starts in the cranial region or on the upper extremities with subsequent generalization. It has been reported that deep brain stimulation of the internal globus pallidus (GPi-DBS) has moderate or unsatisfactory effects in these patients.2,3 We describe a novel mutation of the THAP1 gene in 2 siblings (a boy and a girl) with a rapid generalization into a life-threatening status dystonicus (SD) in the boy. Unlike in the 7 previously reported patients,2,3 in his case, we observed excellent long-term effects from bilateral GPi-DBS.

Beneficial effect of deep brain stimulation of GPi in a patient with dystonia-deafness phenotype.

We present the first case of the successful treatment of dystonia-deafness syndrome by deep brain stimulation (DBS) of the globus pallidus interna (GPi). The case concerns a 30-year-old male patient who had a negative family history of dystonia or hearing loss. At about 3 years of age, he was found to have a severe sensorineuronal hearing impairment, which remained stable until the age of 24. At that time, the patient noticed occasional involuntary twisting of his head toward left. The hearing impairment progressed to total deafness. Notably, there was no previous exposure to neuroleptics until 28 years of age, when he had a psychotic episode with paranoid delusions. The deafness and severe truncal and cervical dystonia accompanied by dysphagia and severe dysarthria further predominated in the clinical picture. Visual evoked potentials were significantly prolonged bilaterally. The ophthalmologic examination and magnetic resonance imaging of the brain were normal. Neuropsychological tests revealed no cognitive deficit. By clinical examination and genetic testing, we ruled out the DYT1, PKAN, Wilson disease, spinocerebellar ataxias, as well as rare syndromes of deafness with generalized dystonia. A comorbidity of primary sporadic non-DYT1 dystonia compounded by deafness due to other causes appeared rather speculative. Finally, severe sensorineuronal hearing disorder from early childhood followed by generalized dystonia developing in early adulthood made us suspect the dystonia-deafness (Mohr-Tranebjaerg) syndrome. Several additional symptoms such as history of behavioral disorder and subclinical involvement of the visual system supported this diagnosis. Even if genetic testing showed no evidence of mutation (frameshift, deletion, stop, missense, splice-site, or intronic mutation) of the gene TIMM8A/DDP1, a novel mutation could not be excluded. Therefore, we still believe that the present case is the dystonia-deafness syndrome. The patient received repeated local injections of botulinum toxin into dystonic neck muscles with only partial relief. Oral treatments by biperidene, tiapride, amantadine, and clonazepam were subsequently given with no or minor improvement. At the age of 29, his cervical and truncal dystonia further progressed with dystonic involvement spreading to his lower extremities. Extreme retrocollis soon led to compromised respiration forcing the patient to sleep in a semirecumbent position. After the failed use of all available pharmacological treatment, we resorted to GPi DBS as to the ultimate option. The patient then had the electrodes (Model 3389, Medtronic, Minneapolis, MN) implanted into the posteroventral portion of the GPi bilaterally. The coordinates of the distal (active) contacts were as follows: 19-mm lateral from the midline in the left and 21-mm lateral in the right hemisphere; 3.5-mm bellow the level of the intercommissural line in the left and 2.5-mm bellow this line in the right hemisphere; and 3-mm anterior to its middle on both sides. A Kinetra neurostimulator was implanted into the subclavicular region. Like in other generalized dystonias, the antidystonic effect of GPi DBS began to show gradually over a course of several months (Fig. 1). Maximum improvement was expressed by a 75% decrease in the motor score of the Burke-FahnMarsden scale (BFMDS), which was reached 10 months after surgery. This is comparable with the effects of GPi DBS commonly seen in patients with DYT1-positive primary dystonia. There was marked abatement of cervical and truncal dystonia as well as improvement of gait (see video). Swallowing and speech showed only little improvement. The hearing loss remained unchanged as expected. As our experience suggests, bilateral GPi DBS can be a suitable symptomatic therapy in patients with the dystonia-deafness phenotype. Now, 21 months after the implantation, the patient is experiencing the stable clinical effects of neurostimulation.

Clinical validity of the Mattis Dementia Rating Scale in differentiating mild cognitive impairment in Parkinson's disease and normative data.

Background/Aims: The aim of the present study was to provide normative data and determine the validity of the Czech version of the Mattis Dementia Rating Scale 2 (czDRS-2) in screening for mild cognitive impairment in Parkinsons disease (PD-MCI) based on the Movement Disorder Society (MDS) Level II criteria. Methods: For validation purposes, 41 healthy controls (HC), 46 patients with PD-NI (Parkinsons disease, no impairment) and 41 patients with PD-MCI (all groups assessed by the MDS Level II criteria for PD-MCI) were matched according to age and education. Results: With screening and diagnostic cutoff scores determined at ≤139 points, the czDRS-2 showed a sensitivity of 78% and a specificity of 88% in the detection of PD-MCI versus HC and a sensitivity of 78% and a specificity of 76% in the detection of PD-MCI versus PD-NI. The AUC (95% confidence interval) for the czDRS-2 was 84% (75-93) and 82% (73-91), respectively. We report percentile values for 286 subjects from the Czech population stratified by education level. Conclusion: Our results show that the czDRS-2 is a valid instrument at Level I for screening PD-MCI and support its construct validity and diagnostic equivalence in a cross-cultural setting.

The Diagnostic Accuracy of Parkinson's Disease Mild Cognitive Impairment Battery Using the Movement Disorder Society Task Force Criteria

The aim of the present study was to provide empirical evidence regarding the classification accuracy of the International Parkinson and Movement Disorder Society (MDS) neuropsychological battery (NB) in the determination of Parkinsons disease mild cognitive impairment (PD‐MCI).

KMT2B rare missense variants in generalized dystonia

Background: Recently a novel syndrome of childhood‐onset generalized dystonia originating from mutations in lysine‐specific methyltransferase 2B (KMT2B) has been reported.

Diffusion tensor imaging in the characterization of multiple system atrophy

Purpose Multiple system atrophy (MSA) is a rare neurodegenerative disease that remains poorly understood, and the diagnosis of MSA continues to be challenging. We endeavored to improve the diagnostic process and understanding of in vivo characteristics of MSA by diffusion tensor imaging (DTI). Materials and methods Twenty MSA subjects, ten parkinsonian dominant (MSA-P), ten cerebellar dominant (MSA-C), and 20 healthy volunteer subjects were recruited. Fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity maps were processed using tract-based spatial statistics. Diffusion data were additionally evaluated in the basal ganglia. A support vector machine was used to assess diagnostic utility, leave-one-out cross-validation in the evaluation of classification schemes, and receiver operating characteristic analyses to determine cutoff values. Results We detected widespread changes in the brain white matter of MSA subjects; however, no group-wise differences were found between MSA-C and MSA-P subgroups. Altered DTI metrics in the putamen and middle cerebellar peduncles were associated with a positive parkinsonian and cerebellar phenotype, respectively. Concerning clinical applicability, we achieved high classification performance on mean diffusivity data in the combined bilateral putamen and middle cerebellar peduncle (accuracy 90.3%±9%, sensitivity 86.5%±11%, and specificity 99.3%±4%). Conclusion DTI in the middle cerebellar peduncle and putamen may be used in the diagnosis of MSA with a high degree of accuracy.

Ataxia telangiectasia gene mutation in isolated segmental dystonia without ataxia and telangiectasia

https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312564-sup-v001_1.htm.

A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder

Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing. We performed trio whole-exome sequencing to identify a de novo essential splice-site variant (c.981+1G>A) in CAMK4, encoding CaMKIV. Through in silico evaluation and cDNA analyses, we demonstrated that c.981+1G>A alters CAMK4 pre-mRNA processing and results in a stable mRNA transcript containing a 77-nt out-of-frame deletion and a premature termination codon within the last exon. The expected protein, p.Lys303Serfs*28, exhibits selective loss of the carboxy-terminal regulatory domain of CaMKIV and bears striking structural resemblance to previously reported synthetic mutants that confer constitutive CaMKIV activity. Biochemical studies in proband-derived cells confirmed an activating effect of c.981+1G>A and indicated that variant-induced excessive CaMKIV signaling is sensitive to pharmacological manipulation. Additionally, we found that variants predicted to cause selective depletion of CaMKIVs regulatory domain are unobserved in diverse catalogs of human variation, thus revealing that c.981+1G>A is a unique molecular event. We propose that our probands phenotype is explainable by a dominant CAMK4 splice-disrupting mutation that acts through a gain-of-function mechanism. Our findings highlight the importance of CAMK4 in human neurodevelopment, provide a foundation for future clinical research of CAMK4, and suggest the CaMKIV signaling pathway as a potential drug target in neurological disease.