**SUMMARY OF SAFETY AND PROBABLE BENEFIT**

**I. General Information**

> Device Generic Name: Implantable multi-programmable quadripolar deep
> brain stimulation system
>
> Device Trade Name: Medtronic Activa^®^ Dystonia Therapy, consisting
> of:
>
> [Model 3307 Activa^®^ Dystonia Therapy Kit]{.underline}:
>
> Model 7426 Soletra Neurostimulator
>
> Model 7482 Extension
>
> Model 3387 DBS^™^ Lead
>
> Model 7452 Control Magnet
>
> [Model 3309 Activa^®^ Dystonia Therapy Kit]{.underline}:
>
> Model 7426 Soletra Neurostimulator
>
> Model 7482 Extension
>
> Model 3389 DBS^™^ Lead
>
> Model 7452 Control Magnet
>
> [Associated Products]{.underline}:
>
> Model 7432 Clinician Programmer
>
> Model 7460 MemoryMod Software Cartridge
>
> Model 8840 N'Vision Clinician Programmer
>
> Model 8870 Application Card
>
> Model 3353/3354 Lead Frame Kit
>
> Model 3625 Test Stimulator
>
> Model 7438 Therapy Controller
>
> Burr Ring Hole and Cap
>
> Applicant's Name and Address: Medtronic Neurological
>
> 710 Medtronic Parkway NE
>
> Minneapolis, MN 55432-5604
>
> Humanitarian Device Exemption (HDE) Number: H020007
>
> Date of Humanitarian Use Device Designation: November 27, 2001
>
> Date of Panel Recommendation: Not applicable.
>
> Date of Good Manufacturing Practices (GMP) Inspection: December 26,
> 2002
>
> Date of notice of Approval to the Applicant: April 15, 2003

**II.** **Indications for Use**

> The Medtronic Activa^^ Dystonia Therapy is indicated for unilateral
> or bilateral stimulation of the internal globus pallidus (GPi) or the
> subthalamic nucleus (STN) to aid in the management of chronic,
> intractable (drug refractory) primary dystonia, including generalized
> and/or segmental dystonia, hemidystonia, and cervical dystonia
> (torticollis) in patients seven years of age or above.
>
> For purposes of this document, the Medtronic Activa^^ Dystonia
> Therapy will be referred to as the Activa^^ System.

**III. Contraindications**

> Implantation of an Activa^^ System is contraindicated for:

-   Patients exposed to diathermy. Do not use shortwave diathermy,
    microwave diathermy or therapeutic ultrasound diathermy (all now
    referred to as diathermy) on patients implanted with a
    neurostimulation system. Energy from diathermy can be transferred
    through the implanted system and can cause tissue damage at the
    location of the implanted electrodes, resulting in severe injury or
    death.

> Diathermy is further prohibited because it can also damage the
> neurostimulation system components resulting in loss of therapy,
> requiring additional surgery for system explantation and replacement.
> Injury or damage can occur during diathermy treatment whether the
> neurostimulation system is turned "on" or "off". Patients should
> inform all their health care professionals that they should not be
> exposed to diathermy treatment.

-   Patients who will be exposed to Magnetic Resonance Imaging (MRI)
    using a full body radio-frequency (RF) coil or a head transmit coil
    that extends over the chest area. Refer to the product labeling for
    comprehensive safety information on the use of MRI in patients with
    implanted Activa systems.

-   Patients who are unable to properly operate the stimulator.

**IV.** **Warnings and Precautions**

> Please refer to the device labeling for a complete list of warnings
> and precautions.
>
> Special Considerations for Pediatric Patients:
>
> Warnings:

-   [Patient growth and lead/extension length]{.underline} -- Evaluate
    the patient's implanted lead/extension assembly for sufficient
    strain relief (e.g., consider patient comfort, range of motion,
    x-ray visualization of the extension) at regular post-implant
    follow-up sessions, especially for patients whose growth is not
    complete at implant. Consideration should be given to replacement of
    the extension with one of greater length during other elective
    surgery procedures, such as during the regular change out of
    neurostimulators that must occur because of battery depletion.

-   [Patient brain growth and lead migration]{.underline} -- Medtronic
    recommends the use of Activa Therapy for individuals with dystonia
    in whom brain growth is approximately 90% complete. In cases where
    growth of the brain and/or skull is not complete at time of implant,
    the distance from the lead anchor point (burr hole) to the target
    site increases with time and growth of the individual. As a result,
    lead migration relative to the target site may occur. If significant
    patient growth and potential resultant lead migration are
    anticipated, this should be considered at the time of initial lead
    placement. The need for frequent programming or the inability to
    control dystonic symptoms may indicate lead migration. Consider
    assessing system performance and potential modifications to the
    therapeutic settings (neurostimulator settings and/or electrode
    configurations). These factors should be considered in the
    establishment of long-term care and follow-up schedules for
    individuals who receive an Activa System at an early age.

-   Children are often engaged in active play and sports activities that
    could damage components of the implanted system. While some degree
    of rough play may be unavoidable, children should be advised to
    avoid games, sports and other pastimes where a strain to the
    lead/connector assembly or a percussive injury to system components
    may be likely to occur (e.g., soccer, football/rugby).

> Precaution:

-   [Dual System Implant]{.underline} - If two neurostimulators are
    implanted, they must be implanted at least 8 inches apart to
    minimize interference. In smaller patients consider placing one
    neurostimulator in the abdomen and one in the chest region. In this
    case, route both lead/extension assemblies and implant both
    neurostimulators on the same side of the body to minimize potential
    electromagnetic interference. A 95-cm extension is recommended to
    connect the lead to the abdominal neurostimulator. Verify final
    programmed parameters by reviewing both devices at the conclusion of
    any programming session.

**V. Device Description**

> The Medtronic Activa® Dystonia Therapy uses an implantable
> neurostimulator to deliver
>
> electrical stimulation to the internal globus pallidus (GPi) or
> subthalamic nucleus (STN) of the brain. The device consists of a lead,
> a neurostimulator, and an extension that connects the lead to the
> neurostimulator. The Medtronic Activa® Dystonia Therapy consists of
> two "kits" comprised of the individual medical device components that
> are required by an implanting physician. The two kits are the Model
> 3307 and the Model 3309 Activa Dystonia Therapy kits. Their contents
> differ only by the model of DBS lead contained within each kit. The
> Activa® Dystonia Therapy kits include a Soletra Model 7426
> Neurostimulator, a Model 7482 Extension, a Model 7452 Control Magnet,
> and either a Model 3387 (Model 3307 kit only) or Model 3389 (Model
> 3309 kit only) lead. Several associated products (listed below) are
> used in conjunction with the Activa® Dystonia Therapy kits but are not
> included in the kit. All contents of the model 3307 and 3309 Activa
> Dystonia Therapy kits and associated products have been approved by
> the FDA within prior Pre-Market Approval (PMA) submissions. A
> description of each of the system components follows.
>
> **[Activa® Dystonia Therapy Kits]{.underline}**
>
> **Model 7426 Soletra Neurostimulator:**
>
> The neurostimulator is implanted subcutaneously in the subclavicular
> or upper abdominal region. It is comprised of a battery and integrated
> circuits that are hermetically sealed within an oval-shaped titanium
> enclosure. The neurostimulator delivers electrical stimulation pulses
> with a variety of parameters, modes, and polarities. A connector
> assembly on the neurostimulator allows connection to the extension.
> The electrical pulses are carried from the neurostimulator to an
> implanted intracerebral lead by means of a lead extension. Four
> setscrews provide electrical contact between the lead/extension and
> the neurostimulator. The stimulation parameters can be non-invasively
> adjusted to optimize control of the symptoms of Dystonia and minimize
> side effects. The adjustments are made via radio-frequency
> communication using the Model 7432 Physician Programmer with the Model
> 8840 N'Vision Programmer. The neurostimulator is battery powered, and
> when the battery is depleted, it can be replaced surgically. The
> frequency of replacement is dependent upon the amount of time the
> neurostimulator is used each day and the stimulation parameters used.
> The neurostimulator case shields are manufactured of titanium with a
> Parylene coating. The connector assembly is manufactured of
> polyurethane with titanium setscrews. Material characterizations and
> toxicity testing have been previously performed on all materials in
> accordance with applicable standards.
>
> **Model 7482 Extension:**
>
> The extension is a set of wires within silicone tubing that connects
> the lead to the neurostimulator, providing an electrical path that
> allows stimulation to be delivered to the target site. The extension
> is subcutaneously passed from the scalp area, where it connects to the
> lead, through to the subclavicular area or upper abdominal region,
> where it connects to the neurostimulator.
>
> **Model 3387/Model 3389 DBS™ Leads:**
>
> The DBS leads consist of a polyurethane protective sheath with four
> 1.5 mm platinum/iridium electrodes near the tip of each lead that
> deliver stimulation to the target site. Lead models include Model
> 3387, in which the 4 electrodes are spaced 1.5 mm apart and Model
> 3389, in which the electrodes are spaced 0.5 mm apart. The leads are
> stereotactically introduced into the target and fixed at the skull
> with a burr hole cap and ring.
>
> **Model 7452 Control Magnet:**
>
> The control magnet allows the patient to turn stimulation on and off.
>
> **[Activa® Dystonia Therapy Associated Products]{.underline}**
>
> **Model 7432 Clinician Programmer:**
>
> The Model 7432 Physician Programmer consists of a printer, programmer,
> and programming head that communicates via telemetry to the
> neurostimulator. Clinicians use the programmer to adjust the
> neurostimulator stimulation parameters and to verify current settings.
>
> **Model 7460 MemoryMod Software Cartridge:**
>
> The Model 7460 MemoryMod Software Cartridge is a plug-in cartridge
> designed to control the specific functions of the Model 7432 Clinician
> Programmer. It contains the necessary software to program the Soletra
> Neurostimulator.
>
> **Model 8840 N'Vision Clinician Programmer:**
>
> The Model 8840 N'Vision Programmer is used with the Model 7432
> Physician Programmer to program the neurostimulator.
>
> **Model 8870 Application Card:**
>
> The Model 8870 Application Card is a plug-in card designed to control
> the specific functions of the Model 8840 N'Vision Clinician
> Programmer. It contains the necessary software to program the Soletra
> Neurostimulator.
>
> **Model 3353/3354 Lead Frame Kits:**
>
> The lead frame kits (which are designed to fit Electa/Leksell and
> Radionics or Radionics-like stereotactic frames) are used to stabilize
> the lead in the insertion cannula during implantation.
>
> **Model 3625 Test Stimulator:**
>
> The test stimulator is used for perioperative testing. Parameters that
> can be adjusted include amplitude, pulse width, rate, and electrode
> selection. The test stimulator enables the physician to evaluate the
> efficacy of neurostimulation for the patient, particularly in relation
> to lead position, during intraoperative testing.
>
> **Model 7438 Therapy Controller:**
>
> The therapy controller is designed for use by a patient or caregiver.
> Using the therapy controller, the patient or caregiver can turn
> therapy on or off, check whether the therapy is on or off, and check
> the condition of the neurostimulator's battery.
>
> **Burr Hole Ring and Cap:**
>
> The burr hole ring is constructed of nylon and the cap is made of
> silicone. The ring has ridges that hold it in place within the burr
> hole in the skull. Troughs are machined into the ring, and when the
> leads are inserted, the burr hole cap secures the lead in one of the
> troughs.

**VI. Alternative Practices or Procedures**

> According to Brin (1998), treatment of primary dystonia includes oral
> medications, injections of therapeutic agents directly into nerve or
> muscle tissue, and surgery. Medical therapy is largely determined by
> the specific diagnosis, based on the clinical categorization and
> etiology, and includes use of anticholinergics, muscle relaxants,
> antiepileptics, and dopamine replacement therapy. Alternative
> treatments include the injection of therapeutic agents leading to
> chemodenervation and neuromuscular blockade. Surgical treatment, only
> recommended for patients who fail to improve with either medication or
> injections, may include lesioning. Physical therapy also plays a
> supplementary role for some patients. Supportive therapy (e.g.,
> counseling, etc.) can help some individuals' psychosocial adjustment
> to the disorder.

**VII. Marketing History**

> Deep brain stimulation (DBS) therapy for dystonia has not been
> commercialized to date. The Medtronic Activa® Tremor Control System
> has been commercially available in Europe, Canada and Australia since
> March 1995 and in the United States (PMA P960009) since August 1997.
> Medtronic Activa Parkinson's Control Therapy has been commercially
> available in Europe since April 1998 and in the United States
> (P960009/S7) since January 2002. Medtronic's Activa System has not
> been withdrawn from the market in any country for reasons related to
> its safety and/or effectiveness.

**VIII. Potential Adverse Effects of the Device on Health**

> **Reported Adverse Effects**
>
> Thirty-four manuscripts on published studies to date were reviewed.
> The studies described consist of non-randomized, non-blinded trials
> involving a total of 201 patients.
>
> Literature described the following adverse events:

-   Hemiplegia/Hemiparesis

-   Worsening of Motor Impairment

> \- Dysphagia

-   Sensory Impairment

-   Speech/Language

-   Subcutaneous Hemorrhage/Seroma

-   Cerebral Spinal Fluid Abnormality

-   General\*

> \- Infection
>
> \- Erosion
>
> \- Lead fractures
>
> \- Hardware Breakage
>
> \- IPG Failure

-   Déjà vu corrected by surgically revised lead placement

-   Irritating cough with stimulation ON

> *\* Includes adverse events related to the system components*
>
> **Potential Adverse Effects**
>
> Additionally, one may reasonably expect the risks associated with the
> use of the Activa system for the approved indications of Parkinson 's
> disease (PD) and Essential Tremor (ET) to be similar in treating
> dystonia. As described in the summary of safety and effectiveness data
> for a supplemental premarket approval application for bilateral
> stimulation of the internal globus pallidus (GPi) or the subthalamic
> nucleus (STN) using Medtronic Activa Parkinson's Control Therapy
> indicated for adjunctive therapy in reducing some of the symptoms of
> advanced, levodopa-responsive Parkinson's disease that are not
> adequately controlled with medication (P960009S007), a description of
> adverse events that may also be applicable for use with dystonia is
> provided from a prospective open label design study (Table 1).
>
> Over the entire study duration, 12/160 patients (7.5%) had
> intracranial hemorrhage; 17/160 patients (10.6%) had device-related
> infection; 16 patients (10.0%) had paresis/asthenia; and 13/160
> patients (8.1%) had hemiplegia/hemiparesis. The rate of
> stimulation-related adverse events was 51.9% (83/160 patients) and the
> rate of ongoing stimulation-related events was 22.5% (36/160
> patients). The rate of serious stimulation-related adverse events was
> 9.4% (15/160) and the rate of ongoing serious stimulation related
> adverse events was 3.1% (5/160) patients. Ongoing serious
> stimulation-related adverse events included: worsening of motor
> impairment/PD symptoms (dyskinesia), sensory impairment (pain); and
> speech/language (dysarthria, hypophonia, and speech disorder). Other
> stimulation related adverse events included: worsening of motor
> impairment/PD symptoms (worse motor fluctuations, incoordination,
> abnormal gait, akinesia/bradykinesia, tremor, rigidity, myoclonus and
> dysphagia); sensory impairment (paresthesia, sensory disturbance,
> hypesthesia, hearing \[tinnitus\] and headache); speech/language
> (voice alteration); eye (visual disturbances \[diplopia, abnormal
> vision and visual field defect\] and eye disorders \[twitching\]);
> cognitive (thinking abnormal, confusion, alteration of mentation
> \[dizziness\]); general (respiratory \[laryngismus\], musculo-skeletal
> \[abnormal posture\], gastrointestinal \[vomiting\], urogenital
> \[urinary incontinence\], metabolic/nutritional \[weight loss\], skin
> and appendages \[sweating\] and systemic \[accidental injury\]; sleep
> \[somnolence and insomnia\]; neuropsychological (psychiatric
> disturbances \[manic reaction and neurosis\]); general
> paresis/asthenia; internal system events (shock/jolt, positioning
> difficulties); cardiovascular (cerebrovascular accident);
> hemiplegia/hemiparesis (asthenia) and depression.
>
> The rate of device-related adverse events was 36.9% (59/160 patients)
> and the rate of ongoing device-related events was 10.0% (16/160
> patients). The rate of serious device-related adverse events was 17.5%
> (28/160 patients) and the rate of ongoing serious device-related
> adverse events was 6.3% (10/160 patients). Ongoing, serious
> device-related adverse events included: internal DBS system events
> (intermittent continuity, electromagnetic interference, and lead
> breakage); infection, worsening of motor impairment/PD symptoms (worse
> motor fluctuations, and incoordination) due to loss of effect; and
> skin and appendages (erosion). Other device-related adverse events
> included: internal DBS system events (shock/jolt, dislodged,
> migration, normal battery failure, malfunction, current leak, wire
> breakage, kinked electrode, electrode problem, positioning
> difficulties, impedance low); external system events (difficult to
> program, printer problem); sensory impairment (pain, sensory
> disturbance, paresthesia and headache); speech/language (hypophonia);
> skin and appendages (skin disorder); subcutaneous hemorrhage/seroma
> (seroma); paresis/asthenia; metabolic/nutritional (edema); and
> cerebral spinal fluid abnormality (pneumocephalus).
>
> One patient experienced manic symptoms (manic reaction) and attention
> and cognitive deficits (thinking abnormal) concurrent with exposure to
> an electronic article surveillance (electromagnetic interference)
> device.
>
> Table 1. Summary of Adverse Events Reported in the Parkinson's Disease
> Clinical Trial

  -----------------------------------------------------------------------------------
  **Adverse Event All Patients                                           
  (n=160)**                                                              
  -------------------------------- ------------ ----------- ------------ ------------
  **Major Category**               **\# of      **Study     **\# (%) of  **95%
                                   Events       Related**   Patients**   CI\*\***
                                   (known                                
                                   serious)**                            

  ***Intracranial Hemorrhage\****  13 (8)       13          12 (7.5)     3.4, 11.6

  ***Device-Related Infection\**** 32 (23)      31          17 (10.6)    5.9, 15.4

  Infection with Explant\*         15 (15)      15          9 (5.6)      2.1, 9.2

  Infection without Explant\*      17 (8)       16          12 (7.5)     3.4, 11.6

  ***Paresis/Asthenia\****         16 (1)       6           16 (10)      5.4, 14.7

  ***Hemiplegia/Hemiparesis\****   15 (8)       10          13 (8.1)     3.9, 12.4

  ***Worsening of Motor            357 (48)     130         110 (68.8)   61.6, 75.9
  Impairment/ PD Symptom\****                                            

  Dyskinesia\*                     131 (22)     64          60 (37.5)    30.0, 45.0

  Worse Motor Fluctuations\*       85 (15)      23          56 (35)      27.6, 42.4

  Abnormal gait\*                  38 (4)       10          30 (18.8)    12.7, 24.8

  Incoordination\*                 33 (3)       14          29 (18.1)    12.2, 24.1

  Tremor\*                         22 (0)       4           18 (11.3)    6.4, 16.2

  Akinesia/Bradykinesia\*          20 (0)       9           19 (11.9)    6.9, 16.9

  Dysphagia\*                      13 (3)       2           12 (7.5)     3.4, 11.6

  Rigidity\*                       13 (1)       3           12 (7.5)     3.4, 11.6

  Myoclonus                        1 (0)        1           1 (0.6)      0, 1.9

  Therapeutic Response, decreased  1 (0)        0           1 (0.6)      0, 1.9

  ***Sensory Impairment\****       148 (14)     59          79 (49.4)    41.6, 57.1

  Pain\*                           71 (5)       15          50 (31.3)    24.1, 38.4

  Paresthesia\*                    37 (1)       23          29 (18.1)    12.2, 24.1

  Sensory Disturbance\*            18 (2)       11          16 (10)      5.4, 14.7

  Headache\*                       16 (4)       8           14 (8.8)     4.4, 13.1

  Neuralgia                        3 (2)        0           3 (1.9)      0, 4.0

  Hearing\*                        2 (0)        1           2 (1.3)      0, 3.0

  Neuropathy                       1 (0)        1           1 (0.6)      0, 1.9

  ***Cognitive\****                142 (21)     61          72 (45)      37.3, 52.7

  Confusion\*                      56 (5)       27          44 (27.5)    20.6, 34.4

  Thinking abnormal\*              39 (3)       16          33 (20.6)    14.4, 26.9

  Hallucinations                   15 (2)       1           11 (6.9)     3.0, 10.8

  Alteration of Mentation\*        16 (5)       9           14 (8.8)     4.4, 13.1

  Amnesia\*                        9 (2)        6           8 (5.0)      1.6, 8.4

  Delusions\*                      5 (4)        0           4 (2.5)      0, 4.9

  Dementia                         2 (0)        2           2 (1.3)      0, 3.0

  ***DBS System\****               93 (33)      80          57 (35.6)    28.2, 43.1

  Internal\*                       86 (33)      74          55 (34.4)    27.0, 41.7

  External\*                       7 (0)        6           6 (3.8)      0.8, 6.7

  ***Speech/Language\****          77 (15)      48          59 (36.9)    29.4, 44.4

  Dysarthria\*                     47 (6)       32          42 (26.3)    19.4, 33.1

  Speech/Language\*                30 (9)       16          23 (14.4)    8.9, 19.8

  ***Neuropsychological\****       55 (18)      6           31 (19.4)    13.3, 26.0

  Psychiatric Disturbances\*       25 (8)       4           14 (8.8)     4.4, 13.1

  Personality Disorder             12 (4)       1           9 (5.6)      2.1, 9.2

  Hostility                        6 (2)        0           5 (3.1)      0.4, 5.8

  Manic Reaction\*                 5 (2)        2           3 (1.9)      0, 4.0

  Neurosis\*                       1 (0)        1           1 (0.6)      0, 1.9

  Paranoid Reaction                1 (0)        0           1 (0.6)      0, 1.9

  Anxiety\*                        25 (7)       2           20 (12.5)    7.4, 17.6

  Apathy                           4 (2)        0           4 (2.5)      0, 4.9

  Suicide Attempt                  1 (1)        0           1 (0.6)      0, 1.9

  ***Depression\****               41 (10)      4           35 (21.9)    15.5, 28.3

  ***Sleep\****                    45 (1)       8           37 (23.1)    16.6, 29.7

  ***Eye\****                      48 (6)       25          39 (24.4)    17.7, 31.0

  Visual Disturbance\*             33 (6)       20          30 (18.8)    12.7, 24.8

  Eye Disorder\*                   10 (0)       5           9 (5.6)      2.1, 9.2

  Eye Infection                    5 (0)        0           4 (2.5)      0, 4.9

  ***Subcutaneous                  15 (6)       10          14 (8.8)     4.4, 13.1
  Hemorrhage/Seroma\****                                                 

  ***Convulsions***                7 (6)        5           7 (4.4)      1.2, 7.5

  ***Death***                      3 (3)        0           3 (1.9)      0, 4.0

  ***Cerebral Spinal Fluid         5 (1)        5           5 (3.1)      0.4, 5.8
  Abnormality***                                                         

  ***General\****                  312 (52)     40          110 (68.8)   61.6, 75.9

  Systemic\*                       75 (14)      7           49 (30.6)    23.5, 37.8

  Gastrointestinal\*               55 (5)       9           41 (25.6)    18.9, 32.4

  Urogenital\*                     53 (7)       3           43 (26.9)    20.0, 33.7

  Respiratory                      43 (10)      8           30 (18.8)    12.7, 24.8

  Metabolic/Nutritional\*          36 (4)       6           29 (18.1)    12.2, 24.1

  Musculo-Skeletal\*               21 (7)       2           19 (11.9)    6.9, 16.9

  Skin and Appendages\*            25 (5)       5           22 (13.8)    8.4, 19.1

  Ecchymosis                       1 (0)        0           1 (0.6)      0, 1.9

  Erosion\*                        3 (3)        2           3 (1.9)      0, 4.0

  Infection, fungal                2 (0)        0           2 (1.3)      0, 3.0

  Lymphedema                       1 (0)        0           1 (0.6)      0, 1.9

  Petechia                         1 (0)        0           1 (0.6)      0, 1.9

  Psoriasis                        1 (1)        0           1 (0.6)      0, 1.9

  Rash                             7 (0)        0           7 (4.4)      1.2, 7.5

  Skin Disorder                    6 (1)        2           6 (3.8)      0.8, 6.7

  Sweating\*                       3 (0)        1           3 (1.9)      0, 4.0

  Ear                              4 (0)        0           4 (2.5)      0, 4.9

  ***Cardiovascular\****           64 (14)      24          32 (20)      13.8, 26.2
  -----------------------------------------------------------------------------------

> *\* Includes adverse events related to the system components.*
>
> *\*\* Note: Exact 95% confidence intervals were used when the \# (%)
> of patients was 0 (0%) because the normal approximation to the
> binomial does not provide a confidence interval. In every other case,
> the normal approximation to the binomial was used to calculate
> confidence intervals.*

**IX. Summary of Preclinical Studies**

> All components of the Medtronic Activa ® Dystonia Therapy have been
> commercially approved for the Medtronic Activa ® Tremor Control System
> (PMA P960009, PMA P960009/S3, PMA P960009/S9, and PMA P960009/S10) and
> Medtronic Activa ® Parkinson's Control Therapy (P960009/S7).
> Therefore, the preclinical testing of these components provided in
> Medtronic Activa® Tremor Control System PMAs and the Medtronic Activa®
> Parkinson's Control Therapy PMA are also applicable to the Medtronic
> Activa ® Dystonia Therapy. No additional bench testing was required to
> qualify the devices for the treatment of dystonia.

**X. Summary of Clinical Information**

> The Medtronic Activa® Dystonia Therapy uses an implantable
> neurostimulator to deliver
>
> electrical stimulation to the internal globus pallidus (GPi), or
> subthalamic nucleus (STN). Neurologists and neurosurgeons have used
> electrical stimulation for more than 35 years as a way to locate and
> distinguish specific sites within the brain. Literature available has
> shown its use in patients with dystonia, and consists of
> retrospective, single institution, unblinded case series that employed
> a variety of classification and rating scales to select patients and
> evaluate outcomes.
>
> **Patient Data Available**
>
> There were 201 patients represented in 34 manuscripts discussing
> specific case studies and outcomes. Patient gender for known cases
> included 83 females (83/201, 41%), 57 males (57/201, 28%), and 61 of
> unknown gender (61/201. 30%). In select case studies where age was
> reported at the time of first surgery, the mean age was 27.7 years
> (range: 5 to 78 years, N=91). Patient age classification at the time
> of first surgery included 21 children, 18 adolescents, 53 adults, and
> 109 of unknown age as shown in Table 2. Eighty-one percent (81%) of
> the pediatric patient population studied (N=21) was above age 7.
>
> Table 2. Age Classification at Surgery in Literature (n=201)

+--------------------+-------------------------------+-----------------+
| **Age              | > **N**                       | > **Average Age |
| Classification**   |                               | > (yrs.)**      |
+--------------------+-------------------------------+-----------------+
| Pediatric (0-12    | > 21                          | > 8.6           |
| yrs.)              |                               |                 |
+--------------------+-------------------------------+-----------------+
| Adolescent (13-17  | > 18                          | > 14.8          |
| yrs.)              |                               |                 |
+--------------------+-------------------------------+-----------------+
| Adult ( \>18 yrs.) | > 53                          | > 39.9          |
+--------------------+-------------------------------+-----------------+
| Unknown            | > 109                         | > \-            |
+--------------------+-------------------------------+-----------------+

> The majority type of dystonia experienced in these patients was
> generalized dystonia (65.2%) as shown in Table 3. There were 34
> patients where the type of dystonia was unspecified.
>
> Table 3. Type of Dystonia in Literature (n=201)

+-----------------------+----------------------+----------------------+
| > **Type of           | > **N**              | > **% (n=201)**      |
| > Dystonia**          |                      |                      |
+=======================+======================+======================+
| > Generalized         | > 131                | > 65.2               |
+-----------------------+----------------------+----------------------+
| > Cervical            | > 17                 | > 8.5                |
+-----------------------+----------------------+----------------------+
| > Hemidystonia        | > 5                  | > 2.5                |
+-----------------------+----------------------+----------------------+
| > Multifocal          | > 3                  | > 1.5                |
+-----------------------+----------------------+----------------------+
| > Segmental           | > 8                  | > 4                  |
+-----------------------+----------------------+----------------------+
| > Cervical (and       | > 1                  | > 0.5                |
| > truncal)            |                      |                      |
+-----------------------+----------------------+----------------------+
| > Focal               | > 1                  | > 0.5                |
+-----------------------+----------------------+----------------------+
| > Dystonic Tremor     | > 1                  | > 0.5                |
+-----------------------+----------------------+----------------------+
| > Unspecified         | > 34                 | > 16.9               |
+-----------------------+----------------------+----------------------+

> The follow-up experience in this literature ranged from 0.7 months to
> 132 months (Average: 12.1 months). Follow-up experience data was
> available on 191 of 201 patients. More than 50% of dystonic patients
> treated with deep brain stimulation participated in greater than 3
> months of follow-up. The stimulation target was primarily the globus
> pallidus internus (bilateral GPi 71.2%, unilateral GPi 6.8%) as shown
> in Table 4.
>
> Table 4. Stimulation Target in Literature (n=201)

+-----------------------+----------------------+-----------------------+
| > **Stimulation       | > **N**              | > **Percent           |
| > Target**            |                      | > (n=205)\***         |
+-----------------------+----------------------+-----------------------+
| > GPi, bilateral      | > 146                | > 71.2                |
+-----------------------+----------------------+-----------------------+
| > GPi, unilateral     | > 14                 | > 6.8                 |
+-----------------------+----------------------+-----------------------+
| > GPi, unspecified    | > 8                  | > 3.9                 |
+-----------------------+----------------------+-----------------------+
| > Pallidal, bilateral | > 1                  | > 0.5                 |
+-----------------------+----------------------+-----------------------+
| > Pallidal,           | > 5                  | > 2.4                 |
| > unspecified         |                      |                       |
+-----------------------+----------------------+-----------------------+
| > STN, bilateral      | > 15                 | > 7.3                 |
+-----------------------+----------------------+-----------------------+
| > VLp, bilateral      | > 7                  | > 3.4                 |
| > posterior           |                      |                       |
+-----------------------+----------------------+-----------------------+
| > VLp, unilateral     | > 6                  | > 2.9                 |
| > posterior           |                      |                       |
+-----------------------+----------------------+-----------------------+
| > Vim, unilateral     | > 1                  | > 0.5                 |
+-----------------------+----------------------+-----------------------+
| > Internal capsule,   | > 1                  | > 0.5                 |
| > thalamic            |                      |                       |
| > interphases,        |                      |                       |
| > bilateral           |                      |                       |
+-----------------------+----------------------+-----------------------+
| > VPL thalamic        | > 1                  | > 0.5                 |
| > nucleus, unilateral |                      |                       |
+-----------------------+----------------------+-----------------------+

> *\* There were 201 patients represented in the 34 manuscripts
> discussing specific case studies and outcomes. Four patients
> experienced multiple surgeries.*

**Patient Outcome**

> Assessment of probable benefit from 3 publications describing more
> than 10 patients shows the following: Coubes et al.(2002a) reported 19
> patients with generalized dystonia positive for the DYT1 mutation,
> with a clinical score improvement of 71% and functional score
> improvement of 63% following one year of therapy; improvement defined
> as the percent decrease between pre- and post-implant motor assessment
> scores (Burke-Fahn-Marsden Dystonia Rating Scale (BFM)). Vidaihet et
> al. (2002) reported 14 primary generalized dystonia patients (with at
> least 6 months follow up) treated with bilateral stimulation. Clinical
> scores were 56 [+]{.underline} 21 pre-operatively and 26
> [+]{.underline} 16 postoperatively (BFM). Broggi et al. (2002)
> reported 10 primary dystonia patients. Eight of the 10 patients
> observed clinical improvement evaluated by BFM, ranging between 27 and
> 88% (up to 6 months follow up); improvement defined as the percent
> decrease between pre- and post-implant motor assessment scores.
>
> [Deep Brain Stimulation Therapy in Children & Adolescents]{.underline}
>
> Eight manuscripts discuss specific outcomes in pediatric populations.
> In the largest series, Coubes et al. (2002a,b) treated dystonic
> children ([\<]{.underline}12 years, N=20) and adolescents (13 to 17
> years, N=14) with deep brain stimulation therapy. Clinical scores
> (BFM) in patients with generalized dystonia positive for the DYT1
> mutation were 61 [+]{.underline} 23 pre-operatively and 21
> [+]{.underline} 21 postoperatively (at 3 months), 11 [+]{.underline}
> 11 postoperatively (at 6 months), and 14 [+]{.underline} 17
> postoperatively (at 12 months).

**XI. Risk Probable Benefit Analysis**

> Limited treatment strategies exist for chronic, intractable (drug
> refractory) primary dystonia, including generalized and/or segmental
> dystonia, hemidystonia, and cervical dystonia (torticollis). The three
> main approaches to the treatment of primary dystonia include systemic
> pharmacological agents (oral medications), local pharmacological
> agents (injected directly into affected muscles or their nerve
> supply), and destructive surgical or neurosurgical intervention. When
> local injection therapy is impractical or unsafe, and when systemic
> medications are not effective or produce unacceptable side effects,
> surgery may be considered. Surgical treatments of dystonia, including
> ablative therapies such as thalamotomies and pallidotomies, are
> irreversible, destructive procedures that can be associated with
> disabling complications. The patient group characterized in the
> Humanitarian Use Device application may also be candidates for deep
> brain stimulation therapy. Although there are a number of serious
> adverse events experienced by patients treated with deep brain
> stimulation, in the absence of therapy, chronic intractable dystonia
> can be very disabling and in some cases, progress to a
> life-threatening stage or constitute a major fixed handicap. When the
> age of dystonia occurs prior to the individual reaching their full
> adult size, the disease not only can affect normal psychosocial
> development (due to ostracization and/or prevention of normal peer
> relationships), but also cause irreparable damage to the skeletal
> system. As the body of the individual is contorted by the disease, the
> skeleton may be placed under constant severe stresses which may cause
> permanent disfigurement.
>
> Risks associated with DBS therapy for dystonia appear to be similar to
> the risks associated with the performance of stereotactic surgery and
> the implantation of DBS systems for currently approved indications
> (Parkinson's Disease and Essential Tremor), except for when used in
> either child or adolescent patient groups. These additional risks
> include the use of general anesthetic instead of local anesthesia
> during implantation, potential lead strains or fractures related to
> elongation of the trunk of the patient (due to normal growth) while
> the length of implanted conductor (from the neurostimulator to the
> burr hole) remains fixed, the risk of lead migration due to patient
> head growth resulting in ineffective stimulation and the added risk of
> children being engaged in active play and sports activities that could
> damage components of the implanted system. The risks of lead strain,
> fracture and migration can be minimized by evaluating the patient's
> implanted lead/extension assembly for sufficient strain relief at
> regular post-implant follow-up sessions and by considering the
> replacement of the extension with one of greater length during other
> elective surgery procedures, such as during the regular change out of
> neurostimulators that must occur because of battery depletion. In
> cases where lead tip displacement may occur due to cranial growth the
> lead tip migration may be accommodated through reprogramming due to
> the number and spacing of the electrode contacts.
>
> Therefore, it is reasonable to conclude that the probable benefit to
> health from using the device for the target population outweighs the
> risk of illness or injury, taking into account the probable risks and
> benefits of currently available devices or alternative forms of
> treatment when used as indicated in accordance with the directions for
> use.

**XII. Panel Recommendation**

> This HDE was not reviewed by an FDA advisory panel. The panel has
> previously reviewed the device that is the subject of this HDE for the
> treatment of Parkinson's disease. This HDE does not raise any
> unanticipated safety issues. Therefore, it was determined that this
> application need not be submitted to the advisory panel.

**XIII. CDRH Decision**

> CDRH has determined that, based on the data submitted in the HDE, that
> the Medtronic Activa^®^ Dystonia Therapy will not expose patients to
> an unreasonable or significant risk or illness or injury, and the
> probable benefit to health from using the device outweighs the risks
> of illness or injury, and issued an approval order on April 15, 2003.

**XIV. Approval Specifications**

> Directions for use: See the Physician\'s Labeling.
>
> Hazards to Health from Use of the Device: See Indications,
> Contraindications, Warnings, Precautions and Adverse Events in the
> labeling.

**XV. References**

> Brin MF, Germano I, Danisi FO, Weisz D, Gracies J-M, Eidelberg D,
> Bucobo J, Olanow, CW. Deep brain stimulation (DBS) of pallidum in
> intractable dystonia. Movement Disorders 1998;13 (Suppl 2):274
> (abstract).
>
> Broggi G, Franzini N, Nardocci N,. Zorzi G, Marras C, Marchetti M.
> Deep brain stimulation in dystonia. Movement Disorders 2002; 17(Suppl
> 5): S282 (abstract).
>
> Coubes P, Echenne B, Cif L, Azais M, Roubertie A, Frerebeau P.
> Electrical stimulation of the internal globus pallidus in generalized
> dystonia. Movement Disorders 2002a; 17(Suppl 5): S6 (abstract).
>
> []{.mark}
>
> Coubes P, Cif L, Azais M, Roubertie A, Hemm S, Diakonova N, Vayssiere
> N, Monnier C, Hardouin E, Ganau A, Tuffery S, Claustre M, Echenne B.
> Traitement des syndromes dystoniques par stimulation electrique
> chronique du globus pallidus interne. Arch Pediatr 2002b; 9(Suppl 2):
> 84-86.

[]{.mark}

> Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Tezenas Du Montcel
> S, Benabid AL. Bilateral pallidal stimulation in primary generalized
> dystonia: Preliminary results of the SpiDY French multicentric Study.
> Movement Disorders 2002; 17(Suppl 5): S185-S186 (abstract).