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dystonia

Dystonia

Neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures.

The movements may resemble a tremor.

see Cervical dystonia.

Classification

Primary dystonia

Secondary dystonia

Refers to dystonia brought on by some identified cause, such as head injury, drug side effect (e.g. tardive dystonia), or neurological disease (e.g. Wilson's disease).

Levodopa Responsive Juvenile Dystonia and Parkinsonism Secondary to SPG11 Mutation.

see Generalized dystonia.

Etiology

The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning (e.g., lead poisoning) or reaction to pharmaceutical drugs, particularly neuroleptics.


Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases.

Meyer et al., we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement 1).


Children with cerebral palsy (CP) can present with severe secondary dystonia with or without associated spasticity of their extremities.

Pathophysiology

Over the past years, research into the neurophysiology of the basal ganglia has provided new insights into the pathophysiology of movement disorders. The presence of pathological oscillations at specific frequencies has been linked to different signs and symptoms in PD and dystonia, suggesting a new model to explain basal ganglia dysfunction. These advances occurred in parallel with improvements in imaging and neurosurgical techniques, both of which having facilitated the more widespread use of DBS to modulate dysfunctional circuits. High-frequency stimulation is thought to disrupt pathological activity in the motor cortex/basal ganglia network; however, it is not easy to explain all of its effects based only on changes in network oscillations 2).

Clinical features

Dystonia is often initiated or worsened by voluntary movements, and symptoms may “overflow” into adjacent muscles.

Treatment

Outcome

Response is better for primary dystonias than for secondary dystonias. 3).

Good responses have also been reportes with subthalamic nucleus deep brain stimulation.

DBS as treatment for medication-refractory dystonia, on the other hand, may increase the risk of suicide in patients. However, reference data of patients without DBS therapy are lacking.

Case series

Schrader et al retrospectively screened the database of patients with dystonia who underwent DBS. Patients with focal, segmental, or generalized dystonia of primary or tardive origin and no gait disorder due to lower limb dystonia before DBS, bilateral pallidal stimulation, and a follow-up for more than 6 months were included. Reports of adverse events were analyzed, and gait abnormalities were scored by comparing preoperative and postoperative video recordings using Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) items 3.10 (gait) and 3.11 (FOG). To assess the role of GPi-DBS in gait abnormalities, DBS was paused for 24 hours. Gait and FOG were assessed 30 minutes, 2 hours, and 24 hours after restarting DBS. Finally, a standardized adjustment algorithm was performed trying to eliminate the gait disorder.

Of a collective of 71 patients with dystonia, 6 presented with a new gait disorder (8.5%; 2 men, 4 women, mean age 61.3 years [48-69 years], 2 craniocervical, 1 DYT-1 segmental, 1 truncal, 2 tardive dystonia). GPi-DBS improved Burke-Fahn-Marsden Dystonia Rating Scale motor score by 54% and disability score by 52%. MDS-UPDRS item 3.10 worsened from 0.5 (±0.8) to 2.0 (±0.9) and item 3.11 from 0 to 2.5 (±0.5). The gait disorder displayed shuffling steps and difficulties with gait initiation and turning. Increasing voltages improved dystonia but triggered FOG, sometimes worsening over a period of a few hours. It vanished within minutes after ceasing DBS. Electrode misplacement was ruled out. In all but one patient, no optimal configuration was found despite extensive testing of settings (monopolar, bipolar, pulse width 60-210 μs, frequency 60-180 Hz). Nevertheless, a compromise between optimal stimulation for dystonia and eliciting FOG was achieved in each case.

A hypokinetic gait disorder with FOG can be a complication of GPi-DBS 4).

1)
Meyer E, Carss KJ, Rankin J, Nichols JM, Grozeva D, Joseph AP, Mencacci NE, Papandreou A, Ng J, Barral S, Ngoh A, Ben-Pazi H, Willemsen MA, Arkadir D, Barnicoat A, Bergman H, Bhate S, Boys A, Darin N, Foulds N, Gutowski N, Hills A, Houlden H, Hurst JA, Israel Z, Kaminska M, Limousin P, Lumsden D, McKee S, Misra S, Mohammed SS, Nakou V, Nicolai J, Nilsson M, Pall H, Peall KJ, Peters GB, Prabhakar P, Reuter MS, Rump P, Segel R, Sinnema M, Smith M, Turnpenny P, White SM, Wieczorek D, Wiethoff S, Wilson BT, Winter G, Wragg C, Pope S, Heales SJ, Morrogh D; UK10K Consortium.; Deciphering Developmental Disorders Study.; NIHR BioResource Rare Diseases Consortium., Pittman A, Carr LJ, Perez-Dueñas B, Lin JP, Reis A, Gahl WA, Toro C, Bhatia KP, Wood NW, Kamsteeg EJ, Chong WK, Gissen P, Topf M, Dale RC, Chubb JR, Raymond FL, Kurian MA. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet. 2016 Dec 19. doi: 10.1038/ng.3740. [Epub ahead of print] PubMed PMID: 27992417.
2)
Guridi J, Alegre M. Oscillatory activity in the basal ganglia and deep brain stimulation. Mov Disord. 2016 Aug 22. doi: 10.1002/mds.26714. [Epub ahead of print] Review. PubMed PMID: 27548437.
3)
Awan NR, Lozano A, Hamani C. Deep brain stimulation: current and future perspectives. Neurosurg Focus. 2009 Jul;27(1):E2. doi: 10.3171/2009.4.FOCUS0982. Review. PubMed PMID: 19569890.
4)
Schrader C, Capelle HH, Kinfe TM, Blahak C, Bäzner H, Lütjens G, Dressler D, Krauss JK. GPi-DBS may induce a hypokinetic gait disorder with freezing of gait in patients with dystonia. Neurology. 2011 Aug 2;77(5):483-8. doi: 10.1212/WNL.0b013e318227b19e. Epub 2011 Jul 20. PubMed PMID: 21775741.
dystonia.txt · Last modified: 2018/08/31 10:50 by administrador