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CSFDynamics
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CSFDynamics
Company Presentation
CSFDynamics
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Introduction
Key persons behind CSFDynamics A/S
MD, Dr.med.sci., University of Aarhus (1976), Specialist in Neurosurgery (1979). Currently employed as Chief Surgeon and Medical Director at PrivatHospitalet Danmark (1992-). Previously Dr. Børgesen was employed as chief neurosurgeon at the University Clinic of Neurosurgery at Rigshospitalet (1988-02), consultant at Arbejdsskadestyrelsen (1987-99), assistant neurologist at Sikringsstyrelsen (1986-87), consultant at the department of neurosurgery at KAS Glostrup (1984-87), consultant at the department of neurosurgery at Borgaspitalin in Iceland (1982-82). Dr. Børgesen is author and co-author of 86 scientific articles
Svend Erik Børgesen Niels Agerlin
MD from the University of Copenhagen (1986), Ph.D. from the University of Copenhagen (1993). Currently employed as Chief Neurosurgeon at the Neurosurgical dept. at KAS Glostrup (2002-). Previously employed as senior resident physician at the Neurosurgical dept. at KAS Glostrup (1997-01), resident physician and senior resident physician at the Neurosurgical dept. and Neurological dept. at Rigshospitalet (1988-96)
CSFDynamics
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Introduction
History of the SinuShuntYear Event
1993 The first animal experiment on dogs took place.
1994-95 Dr. Børgesen finished the first technical development of the SinuShunt and prepared the shunt ready for patenting.
26 Sep. 1996 An APCT application was filed for the USA, all of Europe, Japan, Hong Kong, Canada and Australia.
1997 The first SinuShunts were implanted.
1997-99 Clinical development and testing of the SinuShunt.
2000 The SinuShunt and the first results were presented at a neurosurgery world congress in Sydney. The interest was overwhelming. At that congress, the first contacts were made with university hospitals in Europe which wanted to participate in the future testing. The development started of a new shunt for treatment of hydrocephalus for infants and young children. At the same time the shunt for treatment of AD was developed.
2001 CSFDynamics entered into a production agreement with Medical Rubber AB in Sweden, a family-owned company established in 1973. The company, which is ISO 9002 and EN 46002 certified and has clean room facilities (class 10,000), currently produces the SinuShunt.
2002 The SinuShunt achieved the CE approval. Pilot testing and clinical studies continued in selected university hospitals in Europe.
Jun. 2003 Dr. Børgesen received the Pudenz Award for 2002 for “Excellence in Cerebrospinal Fluid Physiology”. The award was given to Dr. Børgesen for “his many contributions over the years to the understanding of factors underlying the clinical physiology of hydrocephalus and his recent innovative studies utilizing the ventriculo-cranial venous sinus methodology for treatment of this condition”.
End of 2003 Approx. 200 SinuShunts were implanted in selected hospitals
2007/2009 Development of a new and improved sinus-tube.
CSFDynamics
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Introduction
The SinuShunt
CSFDynamics
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Introduction
Illustration of the SinuShunt principle
CSFDynamics
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Introduction
The SinuShunt vs. traditional shunts
SinuShunt Traditional shunts
CSFDynamics
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Hydrocephalus
CSFDynamics
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Hydrocephalus occurs when there is an imbalance between the CSF produced and the rate at which it is drained
Hydrocephalus that is present at birth is thought to be caused by a complex interaction of various factors and perhaps generic factors
Acquired hydrocephalus may result from intraventricular hemorrhage, meningitis, head trauma, tumours and cysts
The common clinical presentation in a child is increasing head size, irritability, failure to feed and vomiting
Motor and general developmental delay, failure to make appropriate visual and social contact are among the most common problems found in children with hydrocephalus
In about 40% of the cases there is excessive head growth. The same percentage applies to fullness of anterior fontanelle. Splayed sutures in 20% and scalp vein dilatation in 15%
In adults symptoms are gate disturbances and dementia
Over the past 25 years the mortality of Hydrocephalus has decreased from 54% to 5%. Intellectual disability has decreased from 62% to 30%
Hydrocephalus
Causes and symptoms of Hydrocephalus
Causes Symptoms
CSFDynamics
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Hydrocephalus
Diagnosis and treatment of Hydrocephalus
It is very important that Hydrocephalus is diagnosed early to minimise morbidity and mortality
In babies and infants it is sufficient to visualise the intracranial structures and ventricles
In older children a CT scan or MRI could be performed. This would further assist in visualising underlying causes if there are any
Conventional ventriculoperitoneal (VP) shunts are designed for treatment of normal or high pressure Hydrocephalus. They aim at shunting CSF past the partially or fully obstructed outflow pathways
CFS is intended to be drained until a certain, predefined intracranial pressure level is reached
75% of Hydrocephalus patients are treated by shunting
3. ventriculostomy is another way of treating Hydrocephalus patients
As the surgical procedure is more complicated than implanting shunts only 25% of patients are treated by 3rd ventriculostomy
Diagnosis Treatment
CSFDynamics
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Hydrocephalus
Two types of Hydrocephalus
Congenital stenosis of the Sylvius Aquaduct
Obstruction of Foramen Magendi
Hypoplasia of the Arachnoidal Granulation
Communicating Communicating (non-
obstructive) hydrocephalus is the situation where there is communication between the ventricular system and the subarachnoid space
The most common cause of this group is post-infective and post-haemorrhagic hydrocephalus
Non-communicating Non-communicating or
obstructive hydrocephalus is where there is no communication between the ventricular system and the subarachnoid space
The most common cause of this category is aqueduct blockage
CSFDynamics
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Hydrocephalus
Hydrocephalus market
The market for Hydrocephalus is widely spread across the globe
67% of the sales are to high cost countries indicating that a large share of the market probably will be willing to pay a premium for the enhanced efficacy of the SinuShunt
North America
33%
Europe24%
Japan & Korea10%
RoW33%
PS Medical (Medtronic)
42%
Codman (J&J)20%
Integra24%
Phoenix5%
Radionics9%
The top 3 manufacturers account for 86% of revenues
All current manufacturers capitalise on technology used for more than 50 years
Competitive dynamicsGeographical sales splitGeographical sales split
CSFDynamics
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Hydrocephalus
Demand for Hydrocephalus products
The SinuShunt is likely to experience high growth
The SinuShunt is likely to achieve high market shares from the very beginning of the product launch as replacements (probably) will be made to the SinuShunt
125,000 new cases of Hydrocephalus every year
Hydrocephalus is believed to occur in about 2 out of 1,000 births
WHO estimates that 125,000 new cases of Hydrocephalus arise each year
An estimated 40,000 operations are completed every year in the US. The cost of an average operation is ~ 1,500 USD. The annual sales to the US market is ~ USD 60 m
Replacement market of 62,500 shunts every year
In addition to the market for new shunts, there is a replacement market
It is estimated that 50% of all traditional shunts will have to be replaced within 5 years
This gives a theoretical replacement market for 62,500 shunts per year
CSFDynamics
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Hydrocephalus
Treatment alternatives
Shunting Immediate effect ~ 100% reliability (although 50%
of current shunts are replaced within 5 years)
~75% of patients are treated by this methodology3. Ventriculostomy
(intracranial procedure) Immediate effect When first developed the
procedure had high mortality and morbidity rates. Today it is a very safe procedure
~25% of patients are treated by this methodology
Drug treatment Initially, it was shown that
Acetazolamide reduced CSF production by the choroid plexus
In a series of Hydrocephalus in immature infants the drug was used and success was claimed as shunts was avoided in 50% of the cases
0% of patients are treated by this methodology
Shunting is the preferred treatment
CSFDynamics
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Hydrocephalus
The shunting principle
Traditional method of shuntingPressure regulated shunt The shunt will open when the
pressure in the head gets too high
Traditional placement of the shunt
Ventriculo-peritoneal shunt From the ventricular
system to the peritoneal cavity
SinuShunt placement of the shuntPassive shunt There is a continuous flow via the
shunt as the pressure in the Sinus is the same as in the brain
Traditional placement of the shunt
Ventriculo-atrial shunt From the ventricular
system to the right atrium
SinuShuntTraditional shunts
SinuShunt placement of the shunt
From the ventricular system to the transverse sinus
CSFDynamics
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Hydrocephalus
Commonly acknowledged shortcomings of traditional shunts*
Late complications
Too many unnecessary technical complications with traditional shunts
Conceptual shortcomings of traditional shunts result in overdrainage
Relatively short lifetime of current shunts
The average lifetime of traditional shunts is unsatisfactory
* FDA conference 8.1.1999 (www.fda.gov/cdrh/stamp)
CSFDynamics
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Proximal drain displacement
8%
Distal drain occlusion
31%
Infection16%
Overdrainage11%
Shunt defect or blocked11%
Proximal obstruction
23%
Hydrocephalus
Complications with traditional shunts
Survey at Rigshospitalet on procedures from 1961-1988
The survey was reported in 1998
2,400 surgical procedures in 870 patients
Other studies indicate 48% re-operations in children within 3 years
Overdrainage related complications45%
CSFDynamics
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Hydrocephalus
Complications of overdrainage
Accumulation of blood and fluids on the surface of the brain
Low pressure complications
VertigoFatigueHeadache
Obvious complications
Frequent block of ventricular drain and shunt
Other complications
By these criteria ~ 40-50% of complications can be attributed to overdrainage
Result
CSFDynamics
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Hydrocephalus
Dependency on posture
Variable pressure The normal pressure inside the head is 10
– 15 cm of water The differing positions complicate the
drainage when using traditional shunts as the pressure in the drain changes substantially
Traditional shunts ShinuShunt
......
0-10 CM
55-75 CM
Supine Standing Supine Standing
Constant differential pressure Withholding the drain in the cranial area
eliminates unnecessary pressure complications
CSFDynamics
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Hydrocephalus
Technical details of the shunting principle
Treatment of high pressure hydrocephalus by low resistance valve, high opening pressure
Supine positionICP = -10P(ts) = ICP - 4 = -14Diff. Press.* = -10-(-14) = 4
Standing positionICP = 10P(ts) = ICP - 4 = 6Diff.press.* = 10-6 = 4
+/- intracranial pressure 4 vs. 4 mmHg
Traditional shunts
SinuShunt
Traditional valves have large intervals for the intracranial pressure
The SinuShunt does not have any interval for the intracranial pressure
÷
Treatment of high pressure hydrocephalus by low resistance valve, low opening pressure
Treatment of high pressure hydrocephalus by low resistance valve, high opening pressure
Treatment of normal pressure hydrocephalus by variable resistance valve
Supine position ICP = 0.4*1 + 8 = 8.4 mmHg ICP = 0.4*1+12 = 12.4 mmHg ICP = 0.4*10 = 4 mmHg
Standing positionHydrostatic force = -600 mm H2OICP = 0.4*1 - 44 = -43.6
ICP = 0.4*1-44.1+12 = -31.7 mmHgHydrostatic force = -600 mm H2OICP = 0.4*10-44 = -40 mmHg
+/- intracranial pressure 8.4 vs. -43.6 mmHg 12.4 vs. -31.7 mmHg 4 vs. -40 mmHg
CSFDynamics
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Hydrocephalus
Dependency on physical activity
At physical activity The pressure in the chest is
increased The blood has problems
entering the chest from the head and the intracranial pressure will rise
The shunt will open and overdrain
Traditional shunts SinuShunt
At physical activity The SinuShunt is
unaffected by the increasing pressure in the chest
Therefore there is no risk of overdrainage
CSFDynamics
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Hydrocephalus
Relatively short lifetime of current shunts
On average 50% of all shunts are replaced within 5 years
Patients are operated 2.7 times on average during their lifetime
80% of all shunt patients are re-operated within 8 years
Main part of shunt failures is due to shunt technology
Copenhagen (N=870)
+ Hakim Orbissigma Prudenz
Surv
ival of
shunts
Lund: Codman Medos (N=583)
Surv
ival of
shunts
CSFDynamics
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Hydrocephalus
Clinical test of shunting to the sinus
Data on 156 implanted shunts Results
Pilot study111 shunts implanted
Sagittal Sinus 43Transverse Sinus 68
Final study45 intact silicone drains implantedPatients aged 18-1Observation time
Mean observation time 160 daysRange 2 – 846 days
Despite the relatively small test the SinuShunt reflects fewer complications than average
Of the 45 intact silicone drains implanted only 6 patients have had the shunt removed
3 patients had infections which is less than with traditional shunts (16% would imply ~ 7 patients)
There are no complications by draining to the transverse sinus
Event
Drain implant
Total
Drilled
canal
Direct
No complications 26 9 35
Drain occluded 0 6 6
Infection 2 1 3
Intraventr. bleed-not shuntrelated
0 1 1
Total 28 17 45
Effect
Hydrocephalus type
Total
Normal pressure
High pressure
Immediate 15 23 38
None 5 0 5
Transitory 1 1 2
Total 21 24 45
CSFDynamics
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Hydrocephalus
Surgical procedure with traditional shunts
General anesthesia is used A small region of the scalp is shaved (cleanness)
and scrubbed with an antiseptic Sterile drapes are placed over the patient Incisions are made in the head and abdominal
areas The shunt tube is placed in the fatty tissue A small hole is made in the scull and the
membranes between the scull and brain are opened
The ventricular end of the shunt is gently passed into the abdominal cavity where the CSF will be absorbed
The incisions are then closed
Surgical procedure
CSFDynamics
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Hydrocephalus
Implanting the SinuShunt
1 2 3 4 2 51 2 3 4 2 5
1) Connector2) Valves3) Pre-chamber4) Resistance
tube5) Drain for the
transverse sinus
Incision marks Position of the transverse sinus
CSFDynamics
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Hydrocephalus
Surgical procedure with the SinuShunt
A neurosurgeon performs the short and uncomplicated procedure
General anesthesia is used A small region of the scalp is
shaved (cleanness) and scrubbed with an antiseptic
Sterile drapes are placed over the patient
Incisions are made in the head The shunt tube is placed in the
fatty tissue A small hole is made in the scull
and the membranes between the scull and brain are opened
The ventricular end of the shunt is gently passed into the transverse sinus where the CSF will be absorbed
The incisions are then closed
Surgical procedure SinuShunt advantages
Compared with traditional shunts the surgical procedure is very simple
The SinuShunt is easy to implant compared with traditional shunts
The SinuShunt only calls for local anesthesia
The operation area is restricted when implanting the SinuShunt which is not the case for traditional shunts
The SinuShunt implant is much faster than the implant of traditional shunts
Few parts are needed for the surgical procedure when the SinuShunt is used
The SinuShunt imitates physiological drainage close to perfectly which is not the case for traditional shunts
Same procedure as when implanting traditional shunts
Simpler procedure than when implanting traditional shunts
CSFDynamics
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Hydrocephalus
The SinuShunt vs. other shunts
General conclusions The SinuShunt is a unique technology
for treatment of AD patients by drainage
The SinuShunt minimises the risk of complications and enhances the quality of the treatment
Characteristics
Codman
Medos
Miethke OSVII Pudenz
DeltaCogni-Shunt
Sinu-Shunt
Type
Pressure regulated X X
Flow/pressure regulated
X X X
Passive X
Opening pressure X X X X X
Antisiphon device X X
Resorption sites
Peritoneum X X X X X
Heart X X X X X
Cranial Venous Sinus X
Susceptible to posture
Posture dependent X X X X X
Posture independent X
Complication possibilities
Prox. drain occl. X X X X X
Shunt house occl. X X X X X
Distal drain occl. X X X X X X
Distal drain disruption
X X X X X
Distal drain displacement
X X X X X
Overdrainage X X X X X
Infection X X X X X X
CogniShunt vs. SinuShunt conclusions The SinuShunt is simpler than the
CogniShunt creating less room for mechanical complications
The SinuShunt is closer to physiological drainage than the CogniShunt
The SinuShunt is simpler due to the natural resorption site
CSFDynamics
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Hydrocephalus
General conclusions of shunting to the sinus
Present technology is not acceptable (cit.: FDA conference*)
There are too many re-operations Every new patient can expect 2.7 operations 80% of all shunts are re-operated within 8 years
The frequency of complications is too high Main part of shunt failures are due to shunt technology
Present shunts are un-physiological
Shunting to the sinus is clearly beneficial The differential pressure over the shunt is
Constant Independent of posture
Imitate normal CSF flow dynamics Resistance equal to normal value
Normal drainage in all situations Effective in all cases of hydrocephalus
Overall conclusions Survey of literature
Literature favours shunting to the sinus
155 reported cases ”western literature”
>6 years of observation Good clinical effect No complications from
occlusion of sinus > 400 cases reported in
Russian literature Transverse sinus
standard procedure
* FDA conference 8.1.1999 (www.fda.gov/cdrh/stamp)
CSFDynamics
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Alzheimer’s Disease
CSFDynamics
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Alzheimer’s Disease
Causes and symptoms of AD
The causes of AD are not fully understood by scientists
One of the key findings is the negative impact of the aggregation of beta-amyloid and tau proteins
Slow onset. At first, the only symptom may be mild forgetfulness
Patients typically start to forget simple everyday tasks
Later the patients loose their ability to speak and write and eventually they require total care
Causes Symptoms
CSFDynamics
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Alzheimer’s Disease
Diagnosis and treatment of AD
Diagnosis is difficult Biopsy of cerebral tissue possible
but risky Diagnosis is typically made too
late as patients are not willing to face problem
However, the future promises better diagnosis of AD (e.g. Neurosearch research)
Some drugs are able to slow the onset of AD of up to 12 months
Revenues from current drugs on the market total USD2.1bn (2004e)
A phase II study of the COGNIShunt has shown stabilising effects on patients with mild/moderate AD
Diagnosis Treatment
CSFDynamics
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-
5,000,000
10,000,000
15,000,000
20,000,000
25,000,000
30,000,000
2004 2010 2020 2030 2040
US Non US
The world market for AD is ~ 15 million persons of whom 4 million are from the US
It is estimated that 10% of people at the age of 65 and older and 50% of people above 85 suffer from AD
The CAGR of the population older than 65 is 1.8% which is well above the 0.2% representing the total population (incl. people older than 65)
Alzheimer’s Disease
Alzheimer’s patient development
CAGR: 1.8%
Source: OECD demographic report and SG Cowen report (march 2004)
-
500
1,000
1,500
2,000
2,500
3,000
2002 2003 2004 2005 2006 2007 2008
Total US market for Alzheimer's
Indexed development if market were to follow the population dev.
CAGR: 19.7%
The total US sales of AD products was USD1.1bn in 2003
The higher CAGR of the expected sales of Alzheimer’s products compared to the development in Alzheimer’s patients reflects better penetration of Alzheimer’s products due to
More efficient products Increased focus from governments
# o
f p
ers
on
s
US
Dm
Development in population above 65 years
Development in AD products sales
CSFDynamics
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Alzheimer’s Disease
Theory behind treating Alzheimer’s disease through shunting of CSF
Aggregation of protein macromolecules in neurons
A Beta proteins Leads to neuronal
damage/cell death
Proteins measurable in CSF
Turnover of CSF too low
Proteins are not removed with the CSF
Treatment of AD by shunting
Artificial and easy outflow of CSF to increase turnover and protein access
MiniShunt can possibly stop and may
even reverse the progression of
Alzheimer’s disease
CSFDynamics
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Alzheimer’s Disease
Evidence from the CogniShunt Phase II clinical trial
0
2
4
6
8
10
12
14
16
18
Baseline 3 mds. 6 mds. 9 mds. 12 mds. Total
116117
115114
115
112 112
106
103
98
85
90
95
100
105
110
115
120
Baseline 3 mds. 6 mds. 9 mds. 12 mds.
AD patients seem to maintain their MDRS score when using the CogniShunt, whereas a substantial decrease in the MDRS score was recorded in the control group
Mean
MD
RS
sco
re
Delt
a m
ean
MD
RS
sco
re
Treated Non treated
Note: MDRS is by many considered as the primary efficacy endpoint for Alzheimer’s tests. The clinical study comprised 29 patients
Source: Assessment of low-flow CSF drainage as a treatment for AD, Silverberg et al. (2002)
The difference between the control group and the treated patients is steadily increasing throughout the test period
Phase II study 29 patients
15 treated14 in control
group Clinical studies
performed by Eunoe have shown that shunting of CSF may halt the progression of Alzheimer’s
Eunoe’s results were published 22. Oct. 2002
MDRS scores Delta MDRS scores
CSFDynamics
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Alzheimer’s Disease
Shortcomings of traditional shunts in Alzheimer’s
+ As the intracranial
pressure for Alzheimer’s patients is normal, traditional shunts tend to shunt too little CSF
Late complications
Too many unnecessary technical complications with traditional shunts
Conceptual shortcomings of traditional shunts result in overdrainage
Relatively short lifetime of current shunts
The average lifetime of traditional shunts is unsatisfactory
Low CSF turnover
Alzheimer’s disease
Hydrocephalus
CSFDynamics
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CSF drainage of AD patients with current shunts is potentially dangerous
Drainage below ICP leads to hyper drainage
Subdural haemorrhage
Hypotensive symptoms
Vertigo Fatigue Headache
Alzheimer’s Disease
Pitfalls of normal csf-drainages
AD patients typically have normal/low ICP
As opposed to Hydrocephalus, AD patients do not have increased pressure
CSF shunting to peritoneal cavity only possible with high resistance shunts to avoid overdrainage
Amount of CSF shunted is limited
CSFDynamics
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Alzheimer’s Disease
Principle of the MiniShunt I
CSF compartmentMacromolecules
Low ICP (<6-8 mmHg)
Sinuses of the craniumLow pressure (4 mmHg)
Normal CSF-outflow route• Resistance results in ICP at normal or low levels•
Macromolecules retained at
outflow channels
MiniShunt with low resistance• CSF seeks outflow with least resistance• Macromolecules
being transferred with CSF
Indicates high resistance
Indicates low resistance
CSFDynamics
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Alzheimer’s Disease
Physics of the MiniShunt
Traditional shuntsHigh pressure
differential requires much higher resistance
MiniShuntLow pressure differential
enables much larger outflow
with no overdrainage
risk
CSFDynamics
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Alzheimer’s Disease
Production of CSF
The production of CSF for Alzheimer patients may be lower than normal
As the CSF is not shunted, the average lifetime of the CSF in the brain is longer compared to the CSF being shunted
Unwanted proteins may be accumulated
CSF production without the MiniShunt
CSF production with the MiniShunt
The production of CSF for Alzheimer patients increases with the MiniShunt
The turnover rate with CSF increases with the MiniShunt
All produced CSF will tend to flow through the shunt instead of via normal channels
CSFDynamics
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Alzheimer’s Disease
Benchmarking AD products
Drugs Traditional shunts
MiniShunt
Effect
Cost
Patient convenience
Side effects
Postpones onset for maximum 12 months
USD1,800-2,400 per year
Often low due to side-effects
Potential severe allergic reactions and other less severe (e.g. nausea, diarrhoea, drowsiness, muscle cramps, insomnia)
Data suggest superiority to drugs
USD1,300 per year (incl. operation over an 8 year period with 80% re-operated)
Low due to irritation of the abdomen
Complications lead to re-operations in 80% of cases after 8 years
Theoretically superior to traditional shunts due to high volume shunting
USD870 per year (incl. operation over an 8 year period with e.g. 20% re-operated)
High
Very few side effects expected
Patient compliance
Problem 100% 100%
CSFDynamics
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Alzheimer’s Disease
Conclusions regarding the MiniShunt
Treatment benefits It has immediate effect It is easy to implant It has no proven side effects It has much fewer complication
possibilities which is especially important to AD patients due to the typical old age
Surgical benefits: The operation area is restricted The operation is fast Few parts are needed for the
operation Clinical tested design of the
MiniShunt
Treatment downsides: None compared to the
benchmark products
Surgical downsides None compared to the
benchmark products
Benefits of the MiniShunt Drawbacks of the MiniShunt