Mirror mirror on the wall who is the smartest doctor of them all?

Mirror mirror on the wall who is the smartest doctor of them all?

Nitin K Sethi, MD

New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, U.S.A.

As a resident in training, I quickly came to the realization that some of my attendings were smarter than others. No matter how vexing the clinical problem these were the few who always knew the answers. I would present the history, examination findings and pertinent labs and voila these master clinicians would be able to put the pieces of the puzzle together. If they did not know the answer right away, they always knew where and how to look for it. What organ system to focus on and what tests to order. They stood out in stark contrast to my other attending, all ‘good’ neurologists but who I frequently found ordering multiple and at times random tests struggling to find answers to what plagued the patient. Eccentric with bedside manners that at times bordered on the theatrical, these master clinicians on the other hand made medicine fun and easy. It was as if they could walk into a patient’s room and smell his disease.
I frequently wondered what set these doctors apart from others. It could not be the medical school or the residency program they graduated from. Few were from Ivy League colleges and a seldom few were known outside the corridors of the institution they served in. On the other hand a good number of the ‘good’ doctors made it to the New York’s best doctors list time and time again. Was it their depth of knowledge? Many of the ‘good’ doctors would quote articles and studies with ease but still came up short at the patient’s bedside. It had to be Factor E (excellence factor) coded by the M (master) gene. Only a chosen few had it.

Now when I am on the other side of the fence teaching residents and fellows in training, I still at times wonder whether master clinicians are born de novo (with copious amounts of Factor E) or whether a chosen few good physicians become master physicians and the rest remain good. A lot has been written about improving residency training. The goal is to produce competent physicians at the end of the training process but can good residents be trained to become master clinicians? Is Factor E teachable and transferable? Does training under the wings of these masters automatically ensure transfer of gene M to the trainee? The field of medicine glitters with examples of master clinicians who taught, mentored and inspired their residents and fellows to become master clinicians themselves. A closer look at these attending teacher-resident trainee relationships is worthy of our attention. The patient’s bedside is your laboratory is the central tenant that master clinicians teach their students encouraging them to spend time at the patient’s bedside hearing their stories with rapt attention for a small detail in the patient’s history may very well be the key which unlocks the whole puzzle. Sherlock Holmes the master sleuth once told his prodigy Dr. Watson “you see but you do not observe”. Blessed with astute powers of observation and an analytical mind master clinicians similarly teach their students that the eyes do not see what the mind does not know. James Parkinson, a master clinician in his own right, in his short monograph titled “The Shaking Palsy” described 6 patients in total, three of whom he simply observed walking on the city streets. Much of the description of the longitudinal course of the illness we now know as Parkinson’s disease was derived from his observations of a single case only. Master clinicians report just not their successes but also their failures. Always remembering and learning from their failures constantly striving to become better they inspire trainees to follow in their footsteps. Knowing all too well that medicine never was nor shall ever be an exact science, they encourage their trainees not to hesitate to think out of the box when confronted with a vexing case. “When you have eliminated the impossible, whatever remains, however improbable, must be the truth” another quote attributed to Sherlock Holmes is well worth remembering. Last but not the least these lone stars of neurology teach their trainees the importance of treating patients with respect and dignity reminding them ever so gently that our patients remain our best teachers.

“He who studies medicine without books sails an uncharted sea, but he who studies medicine without patients does not go to sea at all.”
(William Osler-Canadian physician 1849-1919)

Epilepsy surgery: just what is it?

In simple terms epilepsy surgery refers to surgery which is carried out to remove the area of the brain which is generating the seizures. Epilepsy surgery though needs careful planning and an extensive diagnostic work-up and hence is usually available only in level IV epilepsy centers. The epileptogenic focus (area of the brain generating the seizure) has to be identified and this is accomplished with the aid of video (continuous) EEG monitoring, at times intracranial EEG monitoring, MRI scans, PET and SPECT scans. Neuropsychological testing and a special test called WADA test is also done which helps to identify the location of language and memory centers in the brain.
After the above testing (some patients may need less, others additional testing), we determine whether a patient is a good surgical candidate, what kind of surgery to offer him and what are the chances that he shall be seizure free after epilepsy surgery.

Nitin K Sethi, MD

Devices in the treatment of epilepsy

Devices in the treatment of epilepsy

Nitin K Sethi, MD

A number of neurostimulation devices are now available for the treatment of medically refractory epilepsy. Medically refractory epilepsy is currently defined as the failure of the patient’s epilepsy to respond to the use of at least 2 frontline and appropriate anti-epileptic drugs (AEDs)) (some physicians use up to 3 drugs) used in a successive fashion.

Types of devices for the treatment of medically refractory epilepsy:

1. Vagus Nerve Stimulator (VNS)
2. Responsive Neurostimulator (RNS)
3. Deep brain stimulator (DBS)

Neurostimulation not a replacement for resective surgical options.

Vagus Nerve Stimulator (VNS): fundamental concepts

1. pacemaker like device to stimulate the Vagus (CN X) nerve.
2. manufactured by Cyberonics Inc, Houston, Tx
3. gained FDA approval in 1997 for the adjunctive treatment of patients over 12 years of age with medically intractable partial onset seizure disorder.
4. Approved in Europe in 1994.
5. simple device consisting of 2 electrodes, an externally programmable pulse generator and a battery pack.
6. the stimulating electrode is implanted around the midcervical portion of the left vagus nerve (composed of 80% afferent fibers) while the impulse generator along with the battery pack is implanted in a subcutaneous pocket in the left infraclavicular region.
7. left vagus nerve is the preferred site of stimulation due to the higher risks of cardiac arrhythmias with right vagus nerve stimulation as it innervates the sinoatrial node and thus influences heart rate and rhythm.
8. the pulse generator is programmed externally through the skin via a magnetic currently hand held wand.
9. different parameters of stimulation can be programmed such as current strength, pulse width, pulse train frequency, current on and off times as well as magnet current strength.
10. a magnet usually worn on the patient’s arm can provide on-demand stimulation.

Mechanism of action of VNS:

1. Not fully elucidated.
2. Vagus nerve has afferent inputs to multiple areas which may be involved in the generation or propagation of ictal activity: reticular formation, thalamus, cerebral cortex.
3. Electrical impulses via the left vagus nerve travel to the nucleus of tractus solitaries (NTS). From the NTS are outflow tracts to reticular formation and locus ceruleus (LC) increasing the release of norepinephrine and serotonin. VNS may thus increase the release of gamma amino butyric acid or inhibit the release of glutamate. Rats in which the LC is destroyed, VNS is no longer effective in controlling seizures.
4. Widespread cortical de-synchronization by the afferent volley of impulses leading to inhibition of recruitment of epileptic discharges may be another mechanism.
5. Alteration of cerebral blood flow (CBF) in specific areas of the brain-not widely accepted.
6. Peripheral stimulation of CN X may modify the epileptic network circuit in the brain by synaptic modulation.
7. Effects on the amygdala likely mediate the antidepressant effects and mood elevating effects of VNS.

Stimulation parameters which can be adjusted:

1. Output current (usual settings are between 1.5 and 2.25 mA)
2. Pulse width (usually between 250-500microsecs)
3. Frequency (usually between 20 to 30 Hz)
4. Time on (usually on for 30 secs)
5. Time off (usually off for 3 to 5 mins)
6. Magnet current (usually set at 0.25 mA above output current)
7. Fast cycling 7 secs on and 14 secs off.
8. Battery life depends upon stimulation settings

Generator models currently available:

1. 102 Pulse
2. 102 Pulse Duo
3. 103 Demipulse
4. 104 Demipulse Duo
5. 105 Aspire HC
6. 106 Aspire SR

Clinical efficacy of VNS:

1. Multiple studies establish the efficacy of VNS in patients with partial onset (focal) epilepsy both in children and adults.
2. Currently FDA approved for adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures that are refractory to antiepileptic medications.
3. Currently FDA approved for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.
4. Used at times for generalized epilepsy but efficacy not established-lack of good quality studies.
5. Case reports showing efficacy in Lennox-Gastaut syndrome (LGS).

Side-effects/ complications of VNS therapy:

1. infection at the generator implantation site.
2. dyspnea, coughing bouts, laryngeal spasms and choking as current is increased.
3. dysphagia, odynophagia as current is increased
4. hoarseness or change in voice
5. thermal injury to the Vagus nerve can occur but is not commonly reported
6. use with caution in patients with COPD and asthma.
7. VNS may worsen pre-existing obstructive sleep apnea (OSA) due to central and peripheral mechanisms by altering the tone of the upper airways mucles.
8. Recommendation is to turn off VNS prior to CPAP titration.

Contraindications of VNS therapy:

1. MRI is not an absolute contraindication.
2. MRI can be carried out-but recommendation is to turn the device off first.
3. Interrogate device both before and after MRI scan.
4. Avoid use of short-wave diathermy, microwave diathermy and devices which generate strong electric or magnetic fields in the vicinity of the VNS.

Responsive Neurostimulation Device (RNS): fundamental concepts

1. Pacemaker like device to stimulate the epileptogenic focus or foci in the brain.
2. manufactured by NeuroPace, Mountain View, California.
3. generator is implanted in a pocket drilled into the skull bone by the neurosurgeon.
4. cortical strip leads and NeuroPace depth leads are implanted onto or into the epileptogenic focus or foci determined by
5. remote monitor and wand used by patient to interrogate device, collect data and upload to the Internet for the physician.
6. programmer and wand used by physician to collect data and program the neurostimulator.
7. a magnet can be swiped over the device to trigger storage of ECoG and also to temporarily stop stimulation.
8. FDA approved as adjunctive therapy in individuals 18 years of age or older with partial onset seizures who have undergone diagnostic testing that localized no more than 2 epileptogenic foci, are refractory to two or more antiepileptic medications, and currently have frequent and disabling seizures (motor partial seizures, complex partial seizures and/or secondarily generalized seizures).
9. Unlike VNS which is an open-loop device, RNS is semi-closed. The device continuously records electrocorticogram (ECoG) and then based on an algorithm can be programmed to deliver brief pulses of electrical stimulation when it detects activity that could lead to a seizure.

Mechanism of action of RNS:

1. rationale for RNS is responsive stimulation of an epileptic focus/ foci in the brain
2. if stimulated in time and with current of appropriate intensity, evolving seizure shall get aborted
3. involves real time electrographic analysis and responsive and automatic delivery of stimulation

Stimulation parameters for RNS:

1. two different epileptogenic foci can be stimulated individually
2. wide range of stimulation settings/parameters that can be adjusted-from 40 to 1000 microseconds, 1 to 333 Hz, 0.5 to 12 mA

Clinical efficacy of RNS:

1. Results similar to other stimulation devices
2. At the end of 2 years, the median seizure reduction was 56%.

Side-effects/ complications of RNS therapy

1. Surgical complications during implantation of device-risk of hemorrhage, infection
2. Lead breakdown/disconnection
3. Replacement of generator requires another craniotomy
4. Patient needs close follow up for stimulation parameters adjustment hence not ideal for patients who live in rural areas or cannot come for regular follow ups.

Deep Brain Stimulator (DBS): fundamental concepts

1. Stimulation of the anterior nucleus of thalamus (ANT)
2. Electrodes implanted bilaterally in the ANT.
3. Stimulator and battery implanted under left clavicle.

Stimulation parameters for DBS:

1. high-frequency stimulation
2. 5 V, 145 pulses per sec, 90 microseconds, cycle time 1 minute on and 5 minutes off

Mechanism of action of DBS:

1. thalamus is a major relay station and thalamocortical networks are widely believed to be involved in seizure propogation by synchronization of ictal activity.
2. stimulation of ANT may cause desynchronization and thus inhibit seizure propogation.
3. in animal experiments low-frequency stimulation leads to EEG synchronization and high-frequency causes EEG desynchronization.

Clinical efficacy of DBS:

1. SANTE (stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy) study-results similar to other stimulation devices.
2. Fourteen patients were seizure-free for 6 months.

Side-effects/ complications of DBS therapy

1. Surgical complications during implantation of device-risk of hemorrhage, infection
2. Lead breakdown/disconnection
3. Replacement of generator requires another craniotomy
4. Patient needs close follow up for stimulation parameters adjustment hence not ideal for patients who live in rural areas or cannot come for regular follow ups.


References

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3. Terra VC, Amorim R, Silvado C, Oliveira AJ, Jorge CL, Faveret E, Ragazzo P, De Paola L. Vagus nerve stimulator in patients with epilepsy: indications and recommendations for use. Arq Neuropsiquiatr. 2013 Nov;71(11):902-6.
4. Meneses MS, Rocha SF, Simão C, Santos HN, Pereira C, Kowacs PA. Vagus nerve stimulation may be a sound therapeutic option in the treatment of refractory epilepsy. Arq Neuropsiquiatr. 2013 Jan;71(1):25-30.
5. Wang DD, Deans AE, Barkovich AJ, Tihan T, Barbaro NM, Garcia PA, Chang EF. Transmantle sign in focal cortical dysplasia: a unique radiological entity with excellent prognosis for seizure control. J Neurosurg. 2013 Feb;118(2):337-44.
6. Spatola M, Jeannet PY, Pollo C, Wider C, Labrum R, Rossetti AO. Effect of vagus nerve stimulation in an adult patient with Dravet syndrome: contribution to sudden unexpected death in epilepsy risk reduction?. Eur Neurol. 2013;69(2):119-21.
7. Aron M, Vlachos-Mayer H, Dorion D. Vocal cord adduction causing obstructive sleep apnea from vagal nerve stimulation: case report. J Pediatr. 2012 May;160(5):868-70.
8. Elliott RE, Morsi A, Kalhorn SP, Marcus J, Sellin J, Kang M, Silverberg A, Rivera E, Geller E, Carlson C, Devinsky O, Doyle WK. Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: long-term outcomes and predictors of response. Epilepsy Behav. 2011 Jan;20(1):57-63.
9. Ashton AK. Depressive relapse after vagal nerve stimulator explantation. Am J Psychiatry. 2010 Jun;167(6):719-20.
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11. Bergey GK, Morrell MJ, Mizrahi EM, Goldman A, King-Stephens D, Nair D, Srinivasan S, Jobst B, Gross RE, Shields DC, Barkley G, Salanova V, Olejniczak P, Cole A, Cash SS, Noe K, Wharen R, Worrell G, Murro AM, Edwards J, Duchowny M, Spencer D, Smith M, Geller E, Gwinn R, Skidmore C, Eisenschenk S, Berg M, Heck C, Van Ness P, Fountain N, Rutecki P, Massey A, O’Donovan C, Labar D, Duckrow RB, Hirsch LJ, Courtney T, Sun FT, Seale CG. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology. 2015 Feb 24;84(8):810-7
12. Cox JH, Seri S, Cavanna AE. Clinical utility of implantable neurostimulation devices as adjunctive treatment of uncontrolled seizures. Neuropsychiatr Dis Treat. 2014 Nov 14;10:2191-200.
13. Morrell MJ. In response: The RNS System multicenter randomized double-blinded controlled trial of responsive cortical stimulation for adjunctive treatment of intractable partial epilepsy: knowledge and insights gained. Epilepsia. 2014 Sep;55(9):1470-1.
14. Heck CN, King-Stephens D, Massey AD, Nair DR, Jobst BC, Barkley GL, Salanova V, Cole AJ, Smith MC, Gwinn RP, Skidmore C, Van Ness PC, Bergey GK, Park YD, Miller I, Geller E, Rutecki PA, Zimmerman R, Spencer DC, Goldman A, Edwards JC, Leiphart JW, Wharen RE, Fessler J, Fountain NB, Worrell GA, Gross RE, Eisenschenk S, Duckrow RB, Hirsch LJ, Bazil C, O’Donovan CA, Sun FT, Courtney TA, Seale CG, Morrell MJ. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial. Epilepsia. 2014 Mar;55(3):432-41.
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Analgesic overuse headache

Recently I saw a patient in the hospital who had complaint of constant severe daily headaches. She was a 34-year-old otherwise healthy African American woman who first developed headaches at the age of 15. At that time she used to get throbbing hemicranial (one half of the head) headaches which were accompanied by nausea. At times she used to throw up if the headache was particularly bad. During the headache episode she complained of light sensitivity (bright lights bothered her, we refer to this as photophobia) perferring to lie in a quiet dark room. Sleep usually aborted her headache attack. She was correctly diagnosed as suffering from common migraine (this is migraine which is not associated with aura) and treated with Inderal (propanolol-a beta blocker). Later she started using Imitrex (a triptan) whenever she had an acute migraine attack. Around the age of 18, she developed pelvic inflammatory disease for which she started using ibuprofen.

At the time of her current presentation, she said her headache character had changed. Now instead of having episodic migraine attacks, she had a headache “all the time”. She was taking 4-6 pills of ibuprofen a day and 8 to 10 Imitrex pills a month.

This brings us to the topic under discussion “analgesic overuse headaches” also at times referred to as “medication overuse headaches”. Research has shown that about 1% of the general population experiences medication overuse headache and the condition is thought to occur due to an interaction between a therapeutic agent (in this case an analgesic) used excessively by a suspectible patient.

The overuse of anti-migraine drugs and analgesics gives rise to a mixed picture of migraine-type and tension-type headaches that occur at least 15 days a month. Patients start taking more and more analgesics to treat the headache and this sets up a vicious cycle of headache-analgesic-headache-analgesic.

Chronic daily headaches due to overuse of analgesics are particularly difficut to treat. Analgesics are discontinued (some patients of course have worsening of their headache during this time). To keep headaches under check during this time (when the analgesics have been discontinued), the doctor may prescribe a low dose tricyclic antidepressant such as Elavil (amitriptyline). The headache usually resolves or reverts to its previous pattern within two months after discontinuation of the drug (analgesic).