TREATMENT OF HUNTINGTON’S DISEASE
ABOUT HUNTINGTON’S DISEASE
Huntington’s disease (HD) is a rare, congenital neurodegenerative disease. It occurs with a frequency of 1.63–9.95 per 100,000 inhabitants of Europe, less often it affects indigenous populations of other continents. Symptomatology includes motor disorders, dementia, and changes in mood and behavior. Huntington’s disease is an autosomal dominant disorder, which means there is a 50% risk for a child to inherit the mutation, regardless of gender. The age of onset of clinical symptoms is variable and difficult to predict. Most often it starts on the 4th-5th decade of life, but cases of onset between the age of 2 and 80 years have been reported. Juvenile form of the disease (JHD – Juvenile Huntington’s Disease) is called Westphal variant, in which the first symptoms appear before the age of 20. This form affects 5-10% of carriers of the mutant gene, and only 1% develop symptoms of Huntington’s disease by the age of 10.
In healthy people, the number of CAG repetitions does not exceed 26. In the case of 36-39 repeats there is incomplete gene penetration, which means that symptoms of Huntington’s chorea may or may not occur. With >39 repeats, gene penetration is complete and development of symptoms is certain. There is a relationship between the age of onset of symptoms and the number of CAG repetitions: in patients with onset of the disease in adulthood, there are on average 40-50 repeats, in the juvenile form>60, and in case of a very early manifestation of the disease – even more than 200. It is believed that the age of onset of the disease is determined by other genes – modulators and environmental factors. Mutation instability during gametogenesis, and especially spermatogenesis, can lead to the phenomenon of anticipation in which the number of CAG repeats in the next generation is multiplied, which is manifested by an earlier onset of symptoms and a more severe course of Huntington’s disease. Thanks to genetic testing by PCR, it is possible to exclude or confirm the carrier state of the mutated gene in an affected person or their relatives with certainty close to 100%. Due to the lack of effective methods of preventing the development of Huntington’s disease, genetic testing is not performed in asymptomatic children under 18 years of age.
Loss of a significant part of neurons, primarily GABAergic medium spiny neurons in the caudate nucleus, which are part of the intermediate pathway of the extrapyramidal system, causes difficulties in stopping movements. This is manifested by chorea. The neurodegenerative process in Huntington’s disease is generalized and also affects the cerebral cortex (especially the layer VI), thalamus, reticulate black matter, upper olive, and deep cerebellar nuclei. As the disease progresses, most of the spiny GABAergic neurons, also those constituting the direct route, disappear, which leads to development of parkinsonian symptoms characteristic of the end-stage disease.
The adult onset form of Huntington’s disease is characterized by a triad of symptoms: involuntary movements, cognitive impairment, and behavioral and mood disorders. These symptoms of Huntington’s disease vary in severity. The spectrum of motor symptoms is wide and includes primarily involuntary movements (chorea), disorders of saccadic eye movements, as well as postural and balance disorders, dystonic movements and myoclonus, dysarthria and dysphagia, and parkinsonian syndrome in the late stage of the disease. Cognitive disorders are of subcortical dementia character and include: attention and executive functions disorders, working memory disorders, thinking stiffness, slowing down the learning process, and selectively impaired ability to recognize negative emotions by patients. There is also a wide spectrum of mental disorders, from depressed mood, increased level of anxiety or irritability through depression, obsessive-compulsive disorders, to paranoid syndromes and repeated suicide attempts.
Among the movement disorders, juvenile Huntington’s disease is characterized by parkinsonian syndrome (stiffness and bradykinesia) rather than chorea. In the Westphal variant, dystonia, ataxia, dysarthria, pyramidal symptoms and epilepsy are also observed much more often than in the classic form. Mood and behavior disorders are the first symptoms of juvenile Huntington’s disease in nearly 1/3 of patients. The spectrum of disorders is wide, ranging from irritability, impulsivity, depressed mood through alcohol and drug addiction to psychotic states with aggressive behavior and depression with suicidal thoughts and attempts.
- Symptoms of Huntington’s disease:
- reduced muscular tonus (increased in Westphal variant)
- dysarthria, dysphagia
- psychiatric (9% of suicides)
- subcortical dementia
HUNTINGTON’S DISEASE COMPREHENSIVE TREATMENT CENTER
CONSULTATION CENTER – qualification procedure
- Pre-qualification for surgical treatment of Huntington’s chorea – online neurosurgery advice – W. Libionka, MD, PhD.
- Qualification for further surgical treatment (DBS) and rehabilitation, including consultations:
- Speech and language therapy
- Neurosurgical -recommendations for further surgical treatment of Huntington’s disease and/or rehabilitation.
- Anesthesiology pre-qualification (in case of qualification for the DBS procedure) – anesthesiologic advice online
CONSULTATION CENTER – treatment monitoring
- Monitoring control – complex (for patients subject to DBS), including consultations:
- neuropsychological- assessment of cognitive deficits,
- speech and language therapy,
- neurosurgical – always the last, with DBS programming)
- Monitoring control – limited (for patients subject to DBS), including consultations:
- neurosurgical- always the last, with DBS programming)
- Monitoring control – complex (for non-DBS patients), including consultations:
- neuropsychological- assessment of cognitive deficits
- speech and language therapy
- Monitoring control – limited (for non- DBS patients), neurological in the outpatient clinic or online advice
In order to ensure optimal stimulator operation (DBS), monitoring control visits 3 and 6 months after the date of the procedure are recommended, and at least every 6 months thereafter.
SURGICAL TREATMENT OF HUNTINGTON’S DISEASE – NEUROSTIMULATION (DBS) – hospital stay for about 5 days
- Verification of the qualification for DBS, including consultations:
- Surgical procedure,
- Periprocedural rehabilitation (physiotherapy and speech and language therapy),
- Post-surgical control (free of charge) within a month after the surgical procedure,
- Based on recommendations from the monitoring control – complex, creating an individual patient rehabilitation program,
- Implementation of the individual rehabilitation program, as a part of 2-3-week rehabilitation courses, with the participation of a physiotherapist, neurologist and neuropsychologist.
INTENSIVE POSTOPERATIVE CARE
A very important component of neurosurgical treatment at our hospital is the Intensive Care Unit (ICU). It is an 8-bed, full-profile intensive care unit, fully equipped with medical monitoring and life-saving equipment for patients in serious conditions, operated by an experienced anesthesiology team led by a specialist in anesthesiology and intensive care. Having the Intensive Care Unit within the Neurosurgery Department guarantees all patients of the Neurosurgery Department the highest possible standard of post-operative care, and in the case of operations to resect brain tumors or to implant brain stimulators, it constitutes an obligatory stage of post-operative treatment.
Why neurostimulation in the treatment of Huntington’s disease?
The immediate future belongs to neurostimulation. Contrary to tissue transplantation, this method has gained wide acceptance, and the number of patients treated with it all over the world amounts to one hundred thousand. The number of scientific publications and new applications of this method is growing rapidly. Clinical trials with the use of neurostimulation in obesity, memory disorders, Alzheimer’s disease, and even disorders of consciousness in patients with craniocerebral trauma are already being conducted. Results obtained are spectacular – patients who remained in a coma-like state for years were awakened, and the results obtained so far indicate that the effect of neurostimulation may be permanent. This is due to the technologically advanced solutions used in stimulators. Each stimulating electrode is equipped with 4 independent contacts with the possibility of separate programming of stimulating current parameters in a unipolar or bipolar configuration (the pulse generator housing acts as an anode in the unipolar configuration). This gives almost 30,000 theoretically possible settings. Thus, in contrast to damaging treatments, in the case of the depletion of effects of neurostimulation, it is usually enough to skillfully re-program the device to obtain clinical improvement.
Why is the procedure preferred to be performed in younger patients?
- Greater, longer-lasting functional improvement
- Greater effect of microlesion and direct improvement after surgery (no severe neuroplastic changes)
- Low perioperative risk, good patient compliance
- Less brain atrophy – greater implant security
- Need for RCT
Mechanism of deep brain stimulation in Huntington’s disease
- Direct effects of stimulation: regional depolarization and hyperpolarisation of the cell membrane (axons – the lowest threshold)
- Indirect (secondary) effects: activation of afferent endings – synaptic effects (stimulation or inhibition of adjacent cells)
- Cathodic or bipolar stimulation (based on immediate neurostimulation effect in Parkinson’s disease and essential tremor):
- 120-180 Hz
- 5-10 Hz – intensifies symptoms
- 10-50 Hz – no improvement
Outcomes of Huntington’s Chorea Treatment
- A total of 30 treatments were performed
- Complete results were obtained in a group of 20 patients operated on in 2015-2019: 15 women and 5 men
- 27 to 50 years (mean 38)
- 4 people with the Westphal variant
- Duration of symptoms from 3 to 8 years (mean 5)
- Inefficiency of pharmacological treatment
- HD confirmation by genetic testing
- FU> 6 months (6-46)
- chorea of the neck, trunk, limbs, facial-mandibular hyperkinesis: 16 patients
- bradykinesia and dystonia: 4
- dysarthria: 16
- dysphagia: 11
- gait disorders: 11
- a moderate subcortical dysfunction in neuropsychological examination
- excluded: endogenous depression, psychosis
- Infections (≈1%)
- Other (<1%)
- Related to patient selection
- Related to errors in imaging methods
- Associated with excess of microelectrodes introduced
- Related to implant failure
- Caused by an electromagnetic field
- Related to the stimulation of adjacent structures
- Severe complications (permanent deficit or death) 2/1000
Outcomes – summary
- Reduction of chorea – 16/16 (100%)
- Reduction of muscle stiffness, dystonia – 4/4 (100%)
- Improvement of dysarthria – 12/16 (75%)
- Reduction of dysphagia – 6/11 (54.5%)
- Reduction of gait disorders – 6/11 (54.5%)
- Bradykinesia – as SE in 2 patients – improvement after LFS
- Improved quality of life 17/20 (85%)
- Effects of stimulation persist in the 50-month follow-up (in the Westphal variant a change of settings was necessary – HFS, LFS, activation of multiple contacts)
- Bilateral simultaneous GPi-GPe stimulation is a safe and effective treatment for chorea in early Huntington’s disease
- A prospective study is planned, with a control group, on the optimal selection of the anatomical target and timing of the procedure, and the effects of stimulation on cognitive, mood and cognitive disorders
The essence of treatment with neurostimulation
The currently used device looks like a pacemaker – it consists of a battery connected to an electric pulse generator, a cable and an electrode. The entire system is implanted subcutaneously: the pulse generator is usually placed below the clavicle and is connected via a cable to a stimulating electrode, surgically implanted in a selected area of the brain. When the procedure is to have a bilateral effect, bilateral electrode implantation is necessary. Once stimulation is on, the flowing current reversibly modifies the activity of the stimulated area, leading to improvement of the patient’s function. The stimulator’s operation is controlled telemetrically by a programmer. There are models enabling percutaneous battery charging by electromagnetic induction already available in the market. This type of device is used in our hospital.
Initially, this method was reserved for patients with the most severe forms of the disease, in whom other, less invasive therapeutic options proved unsuccessful. Currently, younger people, at an earlier stage of the disease, are more and more often qualified for the treatment. In their cases stimulation may provide greater benefits and even slow the progression of Huntington’s disease.
Boston Scientific stimulator
For the neurostimulation of deep brain structures in Huntington’s disease, we use the Vercise Gevia rechargeable stimulator:
- Up to 25 years of uninterrupted operation without battery replacement
- Lower weight and size of the device, the patient experiences less discomfort after implantation
- MRI examinations may be safely performed
- Inductive charging every 1 – 3 weeks
- Wireless remote control for monitoring of the device operation
The use of directional electrodes for electrostimulation of deep brain structures allows for:
- Lower energy consumption
- In case of rechargeable stimulators that extends the time of operation between charging
- In case of non-rechargeable stimulators that extends the time of operation before the necessary replacement
- Increased effectiveness of electrostimulation by directional (over a sector of 120°) effect on selected structures of the brain.
- MRI examination
- Planning the implantation trajectory
- Fixing the stereotactic frame
- MRI image fusion and determination of stereotaxic coordinates
- Preparation of the operating room
- Patient positioning and preparation of the operating field
- Verification of the correct positioning of the frame on the phantom
- Skin incision, skull opening and Stimlock system fixation
- Implantation of the final electrode and verification of its position
- Implantation of the stimulator
The electrode implantation procedure is performed in analgesia and sedation (after intravenous administration of sedatives and painkillers), after attaching a special stereotactic frame to the patient’s head (a device enabling precise insertion of electrodes into the brain), onto which images from the magnetic resonance imaging test performed on the day of the procedure when the frame was already fixed to the patient’s head are projected. Spatial visualization of the inside of the skull obtained this way allows, with the help of computer software, precise targeting (most often the pale globe is the target) and selection of a safe path to lead electrodes in (in a straight line, due to their shape; avoiding blood vessels, grooves and ventricles).
- Planning a DBS procedure is based on an innovative method of examining a patient with a stereotactic frame – in MRI only, which allows for a significant increase in the precision of brain electrode implantation with a maximum deviation of 0.3 mm from the planned target.
Test electrodes (usually 2, thickness of a human hair) are inserted into the brain in the frontal area, above the hairline (so that the hair covered any scars), through a trepanation hole made there. The bioelectric activity of the pale globe, as seen in EEG monitoring, marks reaching the target. Now, the most favorable stimulation site is selected, which requires cooperation with the patient (he or she follows certain commands, e.g. clenching and opening the hand). Once established, the test electrode set is withdrawn and the final (permanent) electrode is installed. In the same way, an electrode is implanted into the other hemisphere of the brain.
- A possibility of using directional electrodes, enabling sectoral (120°) electrostimulation, which improves efficiency.
- As standard, 8 contact electrodes are implanted, operating omnidirectionally (360°), enabling electrostimulation of various layers of the brain within the range of 15.5 mm.
The last stage of the treatment is performed under general anesthesia. The patient is laid in the supine position (previous procedures were done in sitting position). This is the stage in which the neurosurgeon guides the electrode wires under the skin of the neck and head in special tunnel guides and connects them to the battery that is implanted subcutaneously in the subclavian area.
- To improve the effects of treatment during hospital stay, we use perioperative rehabilitation.
- Results of the procedure are assessed during a free postoperative control visit, up to 1 month after the surgery.
REHABILITATION IN TREATMENT OF HUNTINGTON’S DISEASE
- Patient rehabilitation is carried out based on recommendations from the monitoring control – complex and the individual rehabilitation program
- The individual rehabilitation program is offered as part of 2-3-week-long rehabilitation courses with the participation of: a physiotherapist, neurologist and neuropsychologist.
- Rehabilitation can be introduced at any stage of Huntington’s disease treatment, particularly after the DBS procedure.
- During rehabilitation, the patient is accommodated in a hotel near the hospital. It is possible to share the room with an accompanying person.