Transcranial pulse stimulation (TPS) with focused extracorporeal shock waves. A new promising non invasive symptomatic treatment of Parkinson's disease. Casuistics and feasibility study

Abstract

Focused low energy extracorporeal shockwaves have been used for the treatment of neurological disorders since 1990, starting with different forms of spasticity. Later, the treatment of spinal cord injuries and unresponsive wakefulness and finally Alzheimer's disease followed. In parallel one patient with Parkinson's disease was treated and observed over 8 years and 3 patients were observed over 40 months. All patients received initially during two weeks 6 sessions of TPS with 6000 focused shock waves each on the regions of interest of the brain with an energy flux density of 0,20 mJ/mm² (Duolith, later Neurolith Storz Medical AG). After this, all patients received a monthly maintenance treatment with one TPS session over the following years. Furthermore, after every twelve months a booster of 6 sessions with TPS during 2 weeks was applicated. After the initial treatment block the disease symptoms improved by over 50% (Unified Parkinson Rating Scale) in all patients. The symptomatic improvements remained stable with this protocol to date in one patient during the follow-up time for 8 years and in the 3 other patients for over 40 years.

Full text

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Transcranial pulse stimulation (TPS) with focused extracorporeal shock
waves. A new promising non invasive symptomatic treatment of Parkinson’s
disease. Casuistics and feasibility study.
Lohse-Busch, Henning, Rheintalklinik, D-79189 Bad Krozingen
Abstract
Focused low energy extracorporeal shockwaves have been used for the treatment of
neurological disorders since 1990, starting with different forms of spasticity. Later, the
treatment of spinal cord injuries and unresponsive wakefulness and finally Alzheimer’s
disease followed. In parallel one patient with Parkinson’s disease was treated and observed
over 8 years and 3 patients were observed over 40 months. All patients received initially
during two weeks 6 sessions of TPS with 6000 focused shock waves each on the regions of
interest of the brain with an energy flux density of 0,20 mJ/mm² (Duolith, later Neurolith
Storz Medical AG). After this, all patients received a monthly maintenance treatment with
one TPS session over the following years. Furthermore, after every twelve months a booster
of 6 sessions with TPS during 2 weeks was applicated.
After the initial treatment block the disease symptoms improved by over 50% (Unified
Parkinson Rating Scale) in all patients. The symptomatic improvements remained stable with
this protocol to date in one patient during the follow-up time for 8 years and in the 3 other
patients for over 40 years.
Key words: brain, extracorporeal shock waves, transcranial puls stimulation, Parkinson
Introduction
Shockwaves have been used in medicine for over 40 years. Meanwhile, low-intensity
shockwaves proved to be effective for the treatment of an increasing number of indications
in, for instants, tendon and muscle pain, non-unions, heart insufficiency, erectile dysfunction
chronic wounds and other indications from aesthetics to finally neurological rehabilitation.
The treatment with focused low energy extracorporeal shock waves (ESWT) of neurological
indications started very early in the 1990s with the treatment of the spasticity of children
with cerebral palsy [1]. In 2005 the first treatments of spinal cord injury [2,3] and of the
brain of patients with unresponsive wakefulness [4] 2005 were put into practice.
The ESWT working principle is the mechanical stimulation of biological processes called
“mechanotransduction” resulting in the following effects:
• Release of nitric oxide (eNO)[5]
• Increased cell wall permeability , blood brain barrier opening [6]
• Increased cell metabolism [7]
• Release of growth factors like VEGF, BMP, TGF-β, GABA, GDNF and BDNF resulting in
angiogenesis [22] and neurogenesis [5, 7]

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• nerve regeneration in the rat [7,8]
• Anti-inflammatory effect [5]
• Vasodilatation [5]
• Stimulation of stem cells (proliferation, migration and differentiation) [9,10]
Despite the diversity of the various systemic influences, it is astonishing that no undesirable
effects have been reported so far.
Parkinson’s disease is the second most common neurodegenerative disease after
Alzheimer’s disease. Typical symptoms are tremor, muscular rigidity, slowness of movement
and difficulty walking. The symptoms of the disease are the result of a dopamine deficit due
to the death of cells mainly in the substantia Nigra, the major source of dopamine.
After 2005, experimental transcranial extracorporeal shock wave therapies of patients with
minimal consciousness (17) were very successful. Nowadays experimental transcranial
extracorporeal shock wave therapy is called “Transcranial Puls Stimulation” (TPS).
Based on the promising results of the minimal consciousness patients, the trials were
expanded to also treat patients with Alzheimer’s and Parkinson’s disease. At the beginning,
the patients were treated with varying treatment rhythms and varying dosage of shock
waves in order to find out a feasible treatment protocol. In 2011 this treatment protocol was
determined with encouraging results for both Alzheimer’s and Parkinson’s disease. Then the
official study with the TPS of Alzheimer’s disease [11] followed.
Method and Material
The TPS uses focused shockwave pulses for the stimulation of the brain tissue. Focused
shockwaves are different from focused ultrasound signals (Fig. 1). Ultrasound is a continuous
train of pulses with a high frequency of typically 1-5 MHz. High intensity focused ultrasound
can heat up the tissue. Conversely, shockwaves are very short, approximately 1 µs pulses
with a very steep leading edge (in the range of 10 ns) and a high amplitude of up to 150
MPa. In spite of the high-pressure amplitude, the average power density is only 0.1 W/cm2
due to the relatively low pulse repetition rate of 5-10 Hz. Thus, there is no heating effect and
no micro lesions result.

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Fig. 1: Shockwave pulse (a) and ultrasound signal (b)
Safety evaluation
For the intracranial application of the shockwaves, the attenuation of the shockwaves due
the propagation through the skull was investigated in a cadaver trial with and without brain
tissue. The shockwave pressure amplitude is reduced down to 35% (a) and the energy flux
density is reduced down to 15% (b). (Fig.2).
a
b

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Fig. 2: Shockwave pulse attenuation by human skull. The pressure amplitude is reduced
down to 35% (a), the energy flux density is reduced down to 15% (b).
Treatment procedure
Four patients with Parkinson’s disease have been treated with TPS in an experimental long-
term feasibility study. The treatment was performed with the device Duolith and later on
Neurolith (Storz Medical AG) and consisted of six sessions over two weeks. During each
session, 6000 pulses with energy flux density of 0.20 mJ/mm2 at 5Hz were applied
homogeneously over the treatment-relevant brain area, i.e. the frontobasal region,
cerebellum and brain stem, especially nucleus Niger, pallidum, striatum and hippocampus.

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Fig. 3: TPS Treatment setup with BodyTrack System (Neurolith, Storz Medical). for navigation
and documentation of the TPS treatment. Personal MRI/CT data is used for the visualization
of the shockwave energy delivered to the treated brain areas. The overlay color (yellow-
green-blue) shows in real time the distribution of the energy delivered. The treatment
handpiece is homogeneously moved over the treated brain areas. Nevertheless, energy is
also delivered to deeper brain structures due to the bell-shaped energy profile.
During the TPS-session the application handpiece is smoothly moved over the head (Fig. 3)
in order to avoid an inappropriate energy cumulation. Coupling ultrasound gel needs to be
applied generously over the treated areas for optimal shockwave transmission through the
scalp hair. It is not necessary to shave the patient’s head. The attenuation due to the gelled
hair remains under 10% at most. The focus depth is approximately 40 mm for the maximum
of energy flux density. Still, the therapeutical depth stretches even deeper into the brain due
to the bell-shaped decrease in shockwave intensity with respect to the focal point.
After the 2 weeks of initial treatment, all patients received a monthly maintenance
treatment with one TPS session over the following years. Furthermore, after every twelve
months a booster of 6 sessions with TPS was administered.
Results
The patient, who has been in treatment for 8 years, is currently 74 years old. His Parkinson’s
disease progress was assessed with the Parkinson Disease Questionnaire (PDQ 39) using all
items. The initially achieved improvement of about 60% has been maintained by regular re-
treatments and yearly booster remained relatively steady over 8 years (Fig. 4). The
medication intake could be reduced after 2 years. In the following years, no increase in
dosage was necessary.

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Fig.4: Patient treated for 8 years with TPS. The Parkinson’s disease progress was assessed
with the Parkinson Disease Questionnaire (PDQ 39), all items. The initially achieved
improvement of about 60% was maintained by the regular re-treatments and remained
relatively steady symptomatic over the 8 years.
The other 3 patients were tested with the Unified Parkinson Rating Scale (UPDRS). All 3
items of the UPDRS decreased by more than 50% within the treatment period and during a
3-month follow-up. (Fig. 5)
Fig. 5: Three patients have been treated successfully for over 3 years. The Parkinson’s
disease status has been evaluated with the Unified Parkinson Rating Scale (UPDRS). The
motoric part, UPDRS, all 3 items decreased by more than 50% over the treatment period.
The improvement has been maintained by regular re-treatments.
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PDQ 39 ALL ITEMS. FOLLOW UP OVER 8
YEARS WITH MONTHLY MAINTENANCE
TREATMENTS. 2012 THE PATIENT WAS 65
YEARS OLD
6,9
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baseline 14 days 3 mont hs 16 mo nths 24 mo nths 40 mont hs
AVERAGE OF ALL ITEMS (Z-VALUES) OF THE
UNIFIED PARKINSON DISEASE RATING
SCALE (UPDRS) N=3
40 MONTHS FOLLOW UP

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During this period, these patients did not need to increase the dosage of their medications.
Subsequently, the uniform improvement between roughly 35% and 45% was maintained
with regular re-treatments and yearly boosters over a period of over more than 40 months.
The TPS treatment was very well tolerated by all patients No negative side effects were
observed.
Discussion
Parkinson’s disease is not curable, but the symptoms can be reduced. A treatment with
different pharmaceuticals exists. Following the progressive development of the disease, the
pharmaceutical intake needs to be increased. Further options are the deep Brain Stimulation
(DBS) [12] with surgically placed microelectrodes (pacemaker). Another possibility is the
coagulation of the tremor initiating cells in the brain stem. Both methods are very invasive.
Nowadays there is also the non-invasively treatment by focused ultrasound with MRI
navigation [13].
Compared to these partly very invasive treatment methods, TPS is a completely non-invasive
and non-destructive treatment method. It mechanically stimulates larger brain areas
resulting in a broad scope of biological effects (see introduction). Thus, the progress of the
disease seems to be partly reversed and temporarily stopped.
Today we can see a very positive development concerning the brain treatment with TPS. In
the beginning of the brain treatment with shockwaves a precise treatment required very
advanced tropographical anatomic skills. For such a treatment nowadays, a newly developed
navigation system (BodyTrack, Storz Medical AG) is used (Fig. 3). It has been integrated in
the mentioned shockwave generator Duoloith and is named Neurolith (Storz Medical AG). It
has been approved since 2018 (CE-mark) for the treatment of the central nervous system of
patients with Alzheimer’s disease. The system can trace the patient’s head and the
handpiece movement in real time and generate a 3D overlay image for the patient’s MRI or
CT data, showing and documenting the location and intensity (color-coded) of the applied
shockwave (TPS). With this device Parkinson patients also can be treated anatomical
precisely.
The casuistics presented here are limited to TPS as a form of treatment for the central
nervous system only. In order to better assess the effectiveness of the treatment, the
number of influencing variables was kept as small as possible. Therefor only the brains of the
patients were treated. However, it should be pointed out that the treatment results are
significantly better if the very densely innervated soles and the interosseous and lumbrical
muscles of the feet are also included in the treatment. Experience showed that the
treatment of the soles with ESWT from plantar with 1500 impulses and an energy flux
density between 0.10 to a maximum of 0.15 mJ/mm² has proven effective. It gives the
patients a better sole-ground contact and helps remarkably against the muscular stiffness of
the lower limbs.
In any case, as it is with every medical treatment, the patient's individual pain threshold
must be taken into account when selecting the energy flux density.

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Our patients were only mildly to moderately affected by the disease. Further research is
needed to observe possible effects of the TPS in severely affected patients.
Conclusions
The Parkinson’s disease treatment with TPS is safe and effective. Nevertheless, regular
maintenance treatment is necessary in order to maintain the symptomatic improvement
after the initial treatment series of two weeks. Then the progress of the disease seems at
least to be decelerated or even stable for years. The broad scope of the shockwave-
stimulated effects in the brain seems to be an interesting and promising extension to the
traditional treatment.
Outpatient treatment
Significant reduction of the symptoms for years
• Free of pain, no side effects
• Not necessary to shave patient’s head
• Very well tolerated by the patients
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