Respiratory dysfunction in ALS
In ALS there is progressive respiratory dysfunction during the course of the disease, which is largely attributable to progressive paralysis and atrophy (muscle wasting) of the diaphragm. The diaphragm, which separates the thorax (chest) anatomically from the abdomen (belly), is the principal respiratory muscle in humans. The muscular work of breathing is produced by a coordinated downward movement of the diaphragm, with elevation of the ribcage at the same time. In ALS, nerve control of the diaphragm and other respiratory muscles is impaired so that respiratory dysfunction can develop. Typical symptoms of diminished respiratory work (hypoventilation) are a disturbance of sleep architecture, daytime drowsiness, cognitive disorders and infections of the upper airways. Hypoventilation thus leads to impairment of quality of life and is the life limiting element in ALS. The methods so far established for treating hypoventilation are mask ventilation (intermittent non invasive ventilation) and tracheotomy (an incision in the windpipe) with mechanical (invasive) ventilation. However, paresis and atrophy of the diaphragm cannot be prevented or slowed by this conventional ventilation therapy.
The diaphragm pacemaker concept consists of electrical stimulation of the diaphragm, which leads to movement and thus produces an “artificial breath“. The electrical stimulus is delivered at the site in the diaphragm where the responsible nerves (phrenic nerve on both sides) are in contact with the diaphragm muscle. The stimulation is given in the regions of the diaphragm where the phrenic nerve branches into the respiratory muscle and forms the nerve muscle connection (direct diaphragm stimulation, DDS). The objective of DDS is to produce a “training effect“ by repeated stimulation of the diaphragm and thus prevent progression of the respiratory dysfunction (conditioning). This is an experimental treatment procedure in ALS and the therapeutic effects are still largely unknown. Experience so far with DDS in ALS suggests that the rate of progression of the respiratory dysfunction can be reduced. It is possible that the need for mask ventilation or invasive ventilation may be delayed. In principle, combined use of mask ventilation in conjunction with DDS is possible. It should be stressed that cure of the ALS or a positive influence on the limb paralysis cannot be achieved with DDS. It is a symptomatic method for treating ALS respiratory dysfunction with the status of an individual attempt at treatment.
Concept of diaphragm stimulation
The basic principle of DDS entails the attachment of 4 electrodes to the underside of the diaphragm via a minimally invasive abdominal surgical procedure. The electrodes are each connected to a cable that passes out through the abdominal wall. The cables can be connected to an electrical stimulator (NeuRx RA/4 system). The stimulator sends electrical impulses to the electrodes in the diaphragm, leading to contraction of the diaphragm. The stimulation system is activated at least 4 times a day for 30 minutes in order to produce contractions of the diaphragm and thus achieve conditioning of this muscle. If this is sufficiently tolerated, the stimulation time can be extended to several hours per day. If there is nocturnal respiratory dysfunction, continuous DDS during the night hours can be of benefit. In this case, DDS goes beyond conditioning and has the character of an attempt at interventional treatment.
Fig. 1 Caption: Basic principle of diaphragm stimulation: diagram of the ribcage and diaphragm (reddish). The stimulator (right) is connected with the diaphragm through a connecting cable and 4 electrodes (blue marking). Electrical stimulation leads to muscle movement of the diaphragm and thus to an artificial breath.
Description of the diaphragm stimulator
The NeuRx RA/4 stimulation system consists of a stimulator with battery, the stimulation electrodes and connecting cables together with a cable connector. The stimulator is located outside the body and can be connected to the previously implanted stimulation electrodes via the connecting cable. The connection between the stimulator and stimulation electrodes is produced only when stimulation is performed (“stimulation session“). When it is not in use, the device is removed so that an additional device does not have to be worn on the body. The stimulator is similar in size to a rather large mobile phone (Fig. 2)
Fig. 2: Stimulator and control unit:
The illustration shows the diaphragm pacemaker stimulator (upper picture). It is operated only by 2 buttons that have to be pressed at the same time (switching on and off). The individual stimulation parameters are set by the doctor using a control unit (lower picture) which can be used to programme the stimulator.
The electrodes are implanted in the diaphragm in a minimally invasive procedure. The operation to implant the electrodes consists of laparoscopy, which is performed by specialist doctors in the surgical department. The operation is performed under general anaesthetic so that there is no consciousness and pain during the procedure. After induction of anaesthesia, several small incisions are made in the skin of the abdomen. These are only a few centimetres long and are suitable for inserting the surgical instruments.
During the laparoscopy, the surgeon and the neurologist perform several trial stimulations of the diaphragm with special instruments. The aim of the trial stimulation is to identify the locations on the diaphragm that show the optimal stimulation effect. It is desirable for electrical stimulation of the diaphragm to produce as strong a contraction as possible. From over 10 trial stimulations, a total of 4 sites are chosen that produce an optimal motor response to electrical stimulation. The final stimulation electrodes are implanted at these sites. 2 electrodes are inserted on the right and 2 on the left side of the diaphragm. Very fine but strong cables are fixed to the stimulation electrodes, which are brought to the exterior through a single exit site and are there connected to the stimulator. The length of the operation depends on individual factors and can take 2 4 hours. The usual operation time is 2.5 3 hours.
Fig. 3: Minimally invasive surgery for implantation of a diaphragm pacemaker. View of the operating field for diaphragm pacemaker implantation using “keyhole surgery“. Instruments are inserted into the abdomen below the diaphragm through small skin incisions and these are used to implant the stimulation electrodes in the muscle of the diaphragm.
Risks and stresses due to the operation
The implantation of electrodes in the diaphragm can lead to pressure equalisation and entry of air into the chest (pneumothorax), which can lead to impairment of respiratory function. In the majority of cases, if the breathing mechanism is impaired by the pneumothorax, aspiration of the excess air in the chest if necessary and possible (intercostal drain). The suction is started during the operation and continued at the bedside for 1 2 days after the operation by means of a suction pump. This is an established and safe method of treating pneumothorax. The frequency of pneumothorax is very high with DDS as the diaphragm is only a few millimetres thick and implantation of the stimulation electrodes can lead very easily to an air leak. Pneumothorax can therefore be expected frequently in association with implantation of a diaphragm pacemaker. Other risks of DDS are infection and injury of the diaphragm. Infections of the implantation sites are extremely rare. DDS has already been practised for over 20 years in other diseases apart from ALS so that there is already broad experience with this method, confirming the very low infection risk. In the rare case of infection, antibiotic therapy is started and removal of the electrodes by a further laparoscopy is necessary. The likelihood of infection at the electrode exit site on the skin is likewise extremely low. Overall, laparoscopy is regarded as a minimally invasive surgical procedure associated with low operation risks. Injury of the diaphragm by the stimulation electrode is possible in principle. Not a single case of diaphragm injury has been described in clinical practice so far. It can be assumed that this is an extremely rare complication overall.
Investigations prior to implantation of the diaphragm pacemaker
In preparation for the planned operation, several diagnostic investigations are required in order to guarantee the safety and effectiveness of the diaphragm stimulation. These investigations are required as part of inpatient treatment and involve hospital admission 2 3 days before the day of surgery.
The following investigations are planned in advance of the operation:
- Test of respiratory capacity (vital capacity)
- Electrocardiography (ECG)
- Chest X ray (X ray of the thorax in two planes)
- Fluoroscopy of the chest (thorax fluoroscopy) to establish diaphragm mobility
- Laboratory tests
- Cardiology opinion
- Anaesthesiology opinion (risk assessment by the anaesthetist)
Duration of hospitalisation
The total duration of inpatient treatment including postoperative intensive care monitoring and treatment on a normal neurological ward involves 3 4 days. Including the period of the preoperative tests, a hospital admission for a total of 6 7 days can be expected. It should be stressed that shortening or extension of the duration of inpatient treatment may be necessary due to individual features.
Follow up care after implantation of the diaphragm pacemaker
On the day of the operation and on the first postoperative day, monitoring in an intensive therapy unit (ITU) may be required. The decision on ITU treatment is taken depending on the individual symptoms and the risk profile. The stimulation system is used for the first time1 2 days after implantation of the stimulation electrodes. A cable connection is set up between the external stimulator and the stimulation electrodes with the corresponding connecting cables. The stimulation parameters (intensity and frequency of stimulation) are then set and checked for tolerability. Possible side effects can be discomfort in the diaphragm (like “touching an electric fence“) or involuntary muscle contraction in the back. The stimulation parameters are set by the neurologist from the ALS department using a special control unit. The patient and his/her relatives then receive training on the following topics:
- Cleaning the skin at the skin exit site
- Cleaning and treating the stimulation cable
- Dealing with the stimulator
- Attaching and removing the cable from the stimulator and changing the battery
- Carrying out a stimulation session
- Recording stimulation in the home environment
Handling the diaphragm pacemaker
The DDS does not result in any restrictions on ordinary daily activities. Washing, including showering and swimming, is fully possible after wound healing is complete. The only restrictions are during the stimulation session as the stimulator has to be worn on the body during this period.
Fig. 4: Detailed view of the stimulator connection:
The stimulation electrodes in the diaphragm are connected with the outside of the body via connecting cables and lead to a socket (orange). The connection to the stimulator can be made at this connector (grey cable).
After instruction in handling the diaphragm pacemaker, you return home with the stimulator. Diaphragm stimulation is carried out by connecting the stimulator to the cables and switching it on. Stimulation can be operated simply by pressing a button. Technical expertise or programming of the device is not required on the part of the patient. The duration of stimulation per use is 30 minutes. At the end of the stimulation, the device is switched off and detached again from the cables. Stimulation is initially performed in this way for 30 minutes 4 times a day ("stimulation session"). If there is greater impairment of respiratory function, the DDS can be intensified and the stimulation parameters can be extended. Stimulation for several hours per day and continuous stimulation during the night are possible. The stimulation times are agreed with the treating neurologist from the ALS outpatient department on an individual basis.
You record the duration of daily stimulation by entering the time it is switched on and off in a diary. You bring this diary to your outpatient visits so that the stimulation times and electrical parameters can be altered if necessary. Following the operation, an outpatient visit will be necessary first at an interval of 1 month. When diaphragm stimulation is established in the further course of the disease, the number of visits is reduced so that greater observation intervals with OPD visits of 3 months are possible.