474 Form

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Medical Policy Vagus Nerve Stimulation
Table of Contents
• Policy: Commercial • Description
• Information Pertaining to All Policies
• Authorization Information • Policy History
• References
• Coding Information

Policy Number: 474 BCBSA Reference Number: 7.01.20 (For Plan internal use only)

Related Policies • Spinal Cord and Dorsal Root Ganglion Stimulation, #472 • Responsive Neurostimulation for the Treatment of Refractory Partial Epilepsy, #716 • Transcranial Magnetic Stimulation as a Treatment of Depression, #297 • Deep Brain Stimulation, #473

Policy
Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity

Vagus nerve stimulation may be considered MEDICALLY NECESSARY as a treatment of medically refractory seizures.

Vagus nerve stimulation is considered INVESTIGATIONAL as a treatment of other conditions, including but not limited to heart failure, upper-limb impairment due to stroke, essential tremor, headaches, rheumatoid arthritis, fibromyalgia, tinnitus and traumatic brain injury.

Vagus nerve stimulation is considered INVESTIGATIONAL as a treatment of psychiatric conditions, including but not limited to depression, treatment resistant depression and obsessive compulsive disorder. Transcutaneous (nonimplantable) vagus nerve stimulation devices are considered INVESTIGATIONAL for all indications.

Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for situations where prior authorization might be required if the procedure is performed outpatient.

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Outpatient Commercial Managed Care (HMO and POS) Prior authorization is not required. Commercial PPO and Indemnity Prior authorization is not required.

CPT Codes / HCPCS Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list.

The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity:

CPT Codes CPT codes:

Code Description 61885 Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array
61886 Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to 2 or more electrode arrays
64553 Percutaneous implantation of neurostimulator electrodes; cranial nerve
64568 Incision for implantation of cranial nerve (eg, vagus nerve) neurostimulator electrode array and pulse generator 95976 Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with simple cranial nerve neurostimulator pulse generator/transmitter programming by physician or other qualified health care professional 95977 Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with complex cranial nerve neurostimulator pulse generator/transmitter programming by physician or other qualified health care professional

The following ICD Diagnosis Codes are considered medically necessary when submitted with the CPT codes above if medical necessity criteria are met:

ICD-10 Diagnosis Codes ICD-10-CM Diagnosis codes: Code Description G40.309 Generalized idiopathic epilepsy and epileptic syndromes, not intractable, without status epilepticus G40.001 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, with status epilepticus G40.009 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, without status epilepticus

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G40.011 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable, with status epilepticus G40.019 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable, without status epilepticus G40.101 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, with status epilepticus G40.109 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, without status epilepticus G40.111 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable, with status epilepticus G40.119 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable, without status epilepticus G40.201 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, with status epilepticus G40.209 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, without status epilepticus G40.211 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable, with status epilepticus G40.219 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable, without status epilepticus G40.301 Generalized idiopathic epilepsy and epileptic syndromes, not intractable, with status epilepticus G40.311 Generalized idiopathic epilepsy and epileptic syndromes, intractable, with status epilepticus G40.319 Generalized idiopathic epilepsy and epileptic syndromes, intractable, without status epilepticus G40.401 Other generalized epilepsy and epileptic syndromes, not intractable, with status epilepticus G40.409 Other generalized epilepsy and epileptic syndromes, not intractable, without status epilepticus G40.411 Other generalized epilepsy and epileptic syndromes, intractable, with status epilepticus G40.419 Other generalized epilepsy and epileptic syndromes, intractable, without status epilepticus G40.42 Cyclin-Dependent Kinase-Like 5 Deficiency Disorder G40.501 Epileptic seizures related to external causes, not intractable, with status epilepticus G40.509 Epileptic seizures related to external causes, not intractable, without status epilepticus G40.801 Other epilepsy, not intractable, with status epilepticus G40.802 Other epilepsy, not intractable, without status epilepticus G40.803 Other epilepsy, intractable, with status epilepticus G40.804 Other epilepsy, intractable, without status epilepticus G40.811 Lennox-Gastaut syndrome, not intractable, with status epilepticus G40.812 Lennox-Gastaut syndrome, not intractable, without status epilepticus G40.813 Lennox-Gastaut syndrome, intractable, with status epilepticus G40.814 Lennox-Gastaut syndrome, intractable, without status epilepticus G40.821 Epileptic spasms, not intractable, with status epilepticus G40.822 Epileptic spasms, not intractable, without status epilepticus G40.823 Epileptic spasms, intractable, with status epilepticus G40.824 Epileptic spasms, intractable, without status epilepticus G40.833 Dravet syndrome, intractable, with status epilepticus G40.834 Dravet syndrome, intractable, without status epilepticus G40.841 KCNQ2-related epilepsy, not intractable, with status epilepticus G40.842 KCNQ2-related epilepsy, not intractable, without status epilepticus G40.843 KCNQ2-related epilepsy, intractable, with status epilepticus G40.844 KCNQ2-related epilepsy, intractable, without status epilepticus

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G40.89 Other seizures G40.901 Epilepsy, unspecified, not intractable, with status epilepticus G40.909 Epilepsy, unspecified, not intractable, without status epilepticus G40.911 Epilepsy, unspecified, intractable, with status epilepticus G40.919 Epilepsy, unspecified, intractable, without status epilepticus G40.A01 Absence epileptic syndrome, not intractable, with status epilepticus G40.A09 Absence epileptic syndrome, not intractable, without status epilepticus G40.A11 Absence epileptic syndrome, intractable, with status epilepticus G40.A19 Absence epileptic syndrome, intractable, without status epilepticus G40.B01 Juvenile myoclonic epilepsy, not intractable, with status epilepticus G40.B09 Juvenile myoclonic epilepsy, not intractable, without status epilepticus G40.B11 Juvenile myoclonic epilepsy, intractable, with status epilepticus G40.B19 Juvenile myoclonic epilepsy, intractable, without status epilepticus G40.C01 Lafora progressive myoclonus epilepsy, not intractable, with status epilepticus G40.C09 Lafora progressive myoclonus epilepsy, not intractable, without status epilepticus G40.C11 Lafora progressive myoclonus epilepsy, intractable, with status epilepticus G40.C19 Lafora progressive myoclonus epilepsy, intractable, without status epilepticus R56.9 Unspecified convulsions

The following HCPCS code is considered investigational for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

HCPCS Codes HCPCS codes:

Code Description E0735 Non-invasive vagus nerve stimulator

Description Vagus nerve stimulation (VNS) was initially investigated as a treatment alternative in patients with medically refractory partial-onset seizures for whom surgery is not recommended or for whom surgery has failed. Over time, the use of VNS has expanded to include generalized seizures, and it has been investigated for a range of other conditions. While the mechanisms for the therapeutic effects of VNS are not fully understood, the basic premise of VNS in the treatment of various conditions is that vagal visceral afferents have a diffuse central nervous system projection, and activation of these pathways has a widespread effect on neuronal excitability. An electrical stimulus is applied to axons of the vagus nerve, which have their cell bodies in the nodose and junctional ganglia and synapse on the nucleus of the solitary tract in the brainstem. From the solitary tract nucleus, vagal afferent pathways project to multiple areas of the brain. VNS may also stimulate vagal efferent pathways that innervate the heart, vocal cords, and other laryngeal and pharyngeal muscles, and provide parasympathetic innervation to the gastrointestinal tract. Other types of implantable vagus nerve stimulators that are placed in contact with the trunks of the vagus nerve at the gastroesophageal junction are not addressed in this evidence review. Summary Stimulation of the vagus nerve can be performed using a pulsed electrical stimulator implanted within the carotid artery sheath. This technique has been proposed as a treatment for refractory seizures, depression, and other disorders. There are also devices available that are implanted at different areas of the vagus nerve. This evidence review also addresses devices that stimulate the vagus nerve transcutaneously.

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Vagus Nerve Stimulation For individuals who have seizures refractory to medical treatment who receive vagus nerve stimulation (VNS), the evidence includes randomized controlled trials (RCTs) and multiple observational studies. Relevant outcomes are symptoms, change in disease status, and functional outcomes. The RCTs have reported significant reductions in seizure frequency for patients with partial-onset seizures. The uncontrolled studies have consistently reported large reductions in a broader range of seizure types in both adults and children. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have treatment-resistant depression who receive VNS, the evidence includes 3 RCTs evaluating the efficacy of implanted VNS for treatment-resistant depression compared to sham, 1 RCT comparing therapeutic to low-dose implanted VNS, nonrandomized comparative studies, and case series. Relevant outcomes are symptoms, change in disease status, and functional outcomes. Two sham- controlled RCTs only reported short-term results and found no significant improvement in the primary outcome. One sham-controlled trial with follow-up through 12 months found no difference in Montgomery- Åsberg Depression Rating Scale (MADRS) time in response between active and sham groups; however, several clinician and self-reported measures of symptom improvement showed a benefit for VNS. The low-dose VNS controlled trial reported no statistically significant differences between the dose groups for change in depression symptom score from baseline. Other available studies are limited by small sample sizes, potential selection and confounding biases, and lack of a control group in the case series. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have chronic heart failure who receive VNS, the evidence includes a systematic review including 4 RCTs and case series. Relevant outcomes are symptoms, change in disease status, and functional outcomes. Meta-analyses of the RCTs evaluating chronic heart failure found significant improvements in New York Heart Association functional class, quality of life, 6-minute walk-test, and N- terminal-pro brain natriuretic peptide levels in patients treated with VNS compared to control. An analysis of the ANTHEM-HF uncontrolled trial evaluated longer-term outcomes of VNS use in chronic heart failure. They found that left ventricular (LV) ejection fraction improved by 18.7%, 19.3%, and 34.4% at 12, 24, and 36 months, respectively, with high-intensity VNS. Individuals with low-intensity VNS only had significant improvement in LV ejection fraction at 24 months (12.3%). The ANTHEM-HFpEF trial found improvements in New York Heart Association functional class, quality of life, and 6-minute walk test distances in patients with preserved ejection fraction and implanted VNS. Although this data is promising, a lack of a no-VNS comparator group precludes drawing conclusions based on findings from the uncontrolled studies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have upper-limb impairment due to stroke who receive VNS, the evidence includes 3 pilot RCTs and a systematic review of these RCTs. Relevant outcomes are symptoms, change in disease status, and functional outcomes. Two RCTs compared VNS plus rehabilitation to rehabilitation alone; 1 failed to show significant improvements for the VNS group on response and function outcomes, but the other, which had a larger patient population, found a significant difference in response and function outcomes. The other RCT compared VNS to sham and found that although VNS significantly improved response rate, there were 3 serious adverse events related to surgery. A systematic review pooling these data found that implanted VNS improved upper limb motor function based on Fugl-Meyer Assessment- Upper Extremity score when compared to control. Longer-term follow-up studies are needed to evaluate long-term efficacy and safety. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For adults with moderate-to-severe rheumatoid arthritis who receive VNS, the evidence includes 1 pilot randomized, sham-controlled trial and 1 multicenter sham-controlled RCT. The pilot RCT in multidrug- refractory RA demonstrated procedural feasibility and safety. The trial reported that American College of Rheumatology Score 20 [ACR20] and Disease Activity Score-28 [DAS28] outcomes were numerically superior for the VNS group; however, these differences were not statistically compared, as the study

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wasn't powered for effectiveness. The pivotal RESET-RA trial was a multicenter, double-blind, sham- controlled RCT with a 12-week blinded period; published peer-reviewed results show a high rate of implant success and low rates of adverse events, but do not report additional outcomes. The manufacturer's IFU reports statistical superiority of implantable VNS over sham for the prespecified primary responder endpoint, ACR20, but no significant differences on secondary clinical and functional outcomes (DAS28, The Clinical Disease Activity Index [CDAI], and Health Assessment Questionnaire Disability Index [HAQ-DI]). Safety across studies was acceptable, with mostly mild stimulation-related events and infrequent surgery-related complications. Evidence for implantable VNS remains limited to a small feasibility RCT that was not powered for efficacy, as well as a single pivotal, sham-controlled trial with outcome assessment only available in manufacturer documents, which has not yet been peer- reviewed. Overall, the certainty of evidence for RA remains limited, and an additional large, peer- reviewed RCT with longer blinded follow-up is warranted. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have other neurologic conditions (eg, essential tremor, headache, fibromyalgia, tinnitus, autism) who receive VNS, the evidence includes case series. Relevant outcomes are symptoms, change in disease status, and functional outcomes. Case series are insufficient to draw conclusions regarding efficacy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Transcutaneous Vagus Nerve Stimulation For individuals with cluster headaches who receive transcutaneous VNS (tVNS; also referred to as noninvasive VNS [nVNS]) to prevent cluster headaches, the evidence includes 1 RCT and 1 systematic review. Relevant outcomes are symptoms, change in disease status, quality of life and functional outcomes. One RCT for prevention of cluster headache showed a reduction in headache frequency but did not include a sham treatment group. The systematic review evaluating the same RCT found that nVNS reduced the frequency of weekly attacks and improved response rates in preventive cluster headache, however the certainty of evidence rated as low. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals with cluster headache who receive nVNS to treat acute cluster headache, the evidence includes RCTs and 1 systematic review. Relevant outcomes are symptoms, change in disease status, quality of life and functional outcomes. The ACT1 and ACT2 RCTs compared nVNS to sham for treatment of acute cluster headache in patients including both chronic and episodic cluster headache. In ACT1, there was no statistically significant difference in the overall population in the proportion of patients with pain score of 0 or 1 at 15 minutes into the first attack and no difference in the proportion of patients who were pain-free at 15 minutes in 50% or more of the attacks. In the episodic cluster headache subgroup (n=85) both outcomes were statistically significant favoring nVNS although the interaction p-value was not reported. In ACT2, the proportion of attacks with pain intensity score of 0 or 1 at 30 minutes was higher for nVNS in the overall population (43% vs. 28%, p=.05) while the proportion of attacks that were pain- free at 15 minutes was similar in the 2 treatment groups in the overall population (14% vs. 12%). However, a statistically significantly higher proportion of attacks in the episodic subgroup (n=27) were pain-free at 15 minutes in the nVNS group compared to sham (48% vs. 6%, p<.01). These studies suggest that people with episodic and chronic cluster headaches may respond differently to acute treatment with nVNS. Studies designed to focus on episodic cluster headache are needed. Quality of life and functional outcomes have not been reported. Treatment periods ranged from only 2 weeks to 1 month with extended open-label follow-up of up to 3 months. There are few adverse events of nVNS and they are mild and transient. The systematic review evaluating the same RCTs found that nVNS did not improve pain freedom, pain relief, or attack duration compared to controls, with certainty of evidence rated low to very low. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

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For individuals with migraine headache who receive nVNS to treat acute migraine headache, the evidence includes 1 RCT and 1 systematic review. Relevant outcomes are symptoms, change in disease status, quality of life and functional outcomes. One RCT has evaluated nVNS for acute treatment of migraine with nVNS in 248 patients with episodic migraine with/without aura. There was not a statistically significant difference in the primary outcome of the proportion of participants who were pain-free without using rescue medication at 120 minutes (30% vs. 20%; p=.07). However, the nVNS group had a higher proportion of patients with decrease in pain from moderate or severe to mild or no pain at 120 minutes (41% vs. 28%; p=.03) and a higher proportion of patients who were pain-free at 120 minutes for 50% or more of their attacks (32% vs. 18%; p=.02). There are few adverse events of nVNS and they are mild and transient. Quality of life and functional outcomes were not reported and the double-blind treatment period was 4 weeks with an additional 4 weeks of open-label treatment. A systematic review evaluating the same RCT found that nVNS reduced short-term pain but provided no sustained benefit for pain freedom relative to control participants, with the certainty of evidence rated as moderate to low. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals with chronic migraine headache who receive nVNS to prevent migraine headache, the evidence includes 3 RCTs and 1 systematic review. Relevant outcomes are symptoms, change in disease status, quality of life and functional outcomes. The EVENT RCT was a feasibility study of prevention of migraine that was not powered to detect differences in efficacy outcomes. It does not demonstrate the efficacy of nVNS for prevention of migraine. The PREMIUM RCT was a phase 3, multicenter, sham-controlled RCT including 341 randomized participants with a 12-week double-blind treatment period. The results of PREMIUM demonstrated that nVNS was not statistically significantly superior to sham with respect to the outcomes of reduction of at least 50% in migraine days from baseline to the last 4 weeks, reduction in number of migraine days from baseline to the last 4 weeks, or acute medication days. The PREMIUM II trial was a multicenter, sham-controlled RCT including 231 randomized participants with a 12-week double-blind treatment period. The trial was terminated early due to the COVID-19 pandemic and results were based on a modified intention-to-treat population that included 113 total participants. Results demonstrated that treatment with nVNS was not statistically significantly superior to sham with respect to the primary outcome of reduction in the number of migraine days per month during weeks 9 through 12, nor other outcomes such as mean change in the number of headache days or acute medication days. However, the percentage of patients with at least a 50% reduction in the number of migraine days was significantly greater in the nVNS group than in the sham group. The systematic review found that nVNS resulted in only small reductions in monthly migraine or headache days compared with sham, and the results did not consistently achieve statistical significance. The certainty of evidence for preventive migraine was judged low to very low. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have other neurologic, psychiatric, or metabolic disorders (eg, epilepsy, depression, schizophrenia, noncluster headache, impaired glucose tolerance, fibromyalgia, stroke) who receive tVNS, the evidence includes RCTs, systematic reviews of these RCTs, and case series for some of the conditions. Relevant outcomes are symptoms, change in disease status, and functional outcomes. The RCTs are all small and have various methodologic problems. None showed definitive efficacy of tVNS in improving patient outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Policy History Date Action 4/2026 Annual policy review. Policy updated with literature review through September 3, 2025; references added. Policy statements updated to include rheumatoid arthritis: Vagus nerve stimulation is considered investigational as a treatment of other conditions, including but not limited to heart failure, upper-limb impairment due to stroke, essential tremor, headaches, rheumatoid arthritis, fibromyalgia, tinnitus and traumatic brain injury.

9/2025 Investigational statements clarified. 9/1/2025 4/2025 Annual policy review. References updated. Policy statements unchanged.

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10/2024 Clarified coding information. 4/2024 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2024 Clarified coding information. 10/2023 Clarified coding information. 4/2023 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 3/2022 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 4/2021 Annual policy review. Description, summary, and references updated. Policy statements unchanged. Clarified coding information. 1/2021 Medicare information removed. See MP #132 Medicare Advantage Management for local coverage determination and national coverage determination reference.
10/2020 Clarified coding changes. 4/2020 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 4/2019 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2019 Clarified coding changes. 6/2018 Annual policy review. No changes to policy statements. 5/2018 New references added from annual policy review. Background and summary clarified. Prior Authorization Information reformatted. 12/2017 Annual policy review. New investigational indications described. Clarified coding information. Effective 3/1/2018.
3/2016 Annual policy review. New references added. 5/2015 Annual policy review. New references added. 8/2014 Annual policy review. New investigational indications described. Effective 8/1/2014. 6/2014 Updated Coding section with ICD10 procedure and diagnosis codes, effective 10/2015. 12/2013
Removed the HCPCS codes (L8680-LL8689) as they do not meet the intent. 10/2013 Removed CPT codes 64569, 64570 as these CPT codes do not apply to the policy. 4/2013 Annual policy review. New references added. 2/2013 Annual policy review. Changes made to policy statements. Effective 2/4/2013.
1/2013 Updated to add new CPT codes 0312T-0317T. 11/2011- 4/2012 Medical policy ICD 10 remediation: Formatting, editing and coding updates. No changes to policy statements.
4/2011 Annual policy review. No changes to policy statements.
1/2011 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements. 1/2010 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements. 1/2009 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements. 1/2008 Annual policy review. No changes to policy statements. 1/2008 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements. 7/2007 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements. 2/2007 Reviewed - Medical Policy Group - Psychiatry and Ophthalmology. No changes to policy statements. 1/2007 Reviewed - Medical Policy Group - Neurology and Neurosurgery. No changes to policy statements.

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Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

References

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