Practice patterns of mitochondrial disease physicians in North America.
Part 2: treatment, care and management
Sumit Parikha,⁎, Amy Goldsteinb, Mary Kay Koenigc, Fernando Scagliad, Gregory M. Ennse, Russell Sanetof,
for the Mitochondrial Medicine Society Clinical Directors Working Group,
Other members of the MMS, Clinical Director's Work Group
Irina Anselm1, Abigail Collins2, Bruce H. Cohen3, Suzanne D. DeBrosse4, David Dimmock5, Marni J. Falk6,
Jaya Ganesh7, Carol Greene8, Andrea L. Gropman9,10, Richard Haas11, Stephen G. Kahler12, John Kamholz13,
Fran Kendall14, Mark S. Korson15, Andre Mattman16, Margherita Milone17, Dmitriy Niyazov18,
Chang-Yong Tsao24, Johan van Hove25, Laurence Walsh26,27, Lynne A. Wolfe28
1Boston Children's Hospital, Boston, MA
2University of Colorado, Denver, School of Medicine, Denver, CO
3NeuroDevelopmental Science Center, Children's Hospital Medical Center of Akron, Akron, OH
4Center for Human Genetics, University Hospitals Case Medical Center, and Case Western Reserve University, Cleveland, OH
5Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
6Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
7Section of Metabolic Diseases, Children's Hospital of Philadelphia, Philadelphia, PA
8University of Maryland Medical Center, Baltimore, MD
9Department of Neurology, Children's National Medical Center, Washington, D.C.
10George Washington University of the Health Sciences, Washington, D.C.
11UCSD Medical Center and Rady Children's Hospital San Diego, La Jolla, CA
12Dept of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR
13Wayne State University, Detroit, MI
14Virtual Medical Practice, LLC, Atlanta, GA
15Tufts Medical Center, Boston, MA
16Adult Metabolic Disease Clinic, Vancouver General Hospital, Vancouver, BC
17Mayo Medical Center, Rochester, MN
18Department of Pediatrics, Ochsner Clinic Foundation, New Orleans, LA
19Department of Neurology, Children's National Medical Center, Washington, DC
20Vanderbilt University School of Medicine, Nashville, TN
21Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada
22Harvard Medical School and Massachusetts General Hospital, Boston, MA
23McMaster University, Hamilton, Ontario
24Nationwide Children’s Hospital, Columbus, OH
25Clinical Genetics & Metabolism, Children's Hospital Colorado, Denver, CO
26Medical and Molecular Genetics and Clinical Pediatrics, Indiana University School of Medicine, Indianapolis, IN
27Riley Hospital for Children, Indianapolis, IN
28National Institutes of Health, Bethesda, MD
aCenter for Child Neurology, Cleveland Clinic Children's Hospital, Cleveland, OH, United States
bDivision of Child Neurology, Children's Hospital of Pittsburgh, Pittsburgh, PA, United States
cDivision of Child & Adolescent Neurology, University of Texas Medical School at Houston, Houston, TX, United States
dDepartment of Molecular and Human Genetics, Baylor College of Medicine & Texas Children's Hospital, Houston, TX, United States
eDepartment of Pediatrics, Division of Medical Genetics, Stanford University Lucile Packard Children's Hospital, Palo Alto, CA, United States
fSeattle Children's Hospital/University of Washington, Seattle, WA, United States
Mitochondrion 13 (2013) 681–687
⁎ Corresponding author at: Cleveland Clinic, 9500 Euclid Avenue, S60, Cleveland, OH 44195, United States. Tel.: +1 216 444 1994.
E-mail address: email@example.com (S. Parikh).
1567-7249/$ – see front matter © 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/mito
a b s t r a c t a r t i c l ei n f o
Received 13 August 2013
received in revised form 10 September 2013
accepted 17 September 2013
Available online 21 September 2013
Mitochondrial medicine is a young subspecialty. Clinicians have limited evidence-based guidelines on which to
formulate clinical decisions regarding diagnosis, treatment and management for patients with mitochondrial
disorders. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for
preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society
(MMS) assessed the current state of clinical practice including diagnosis, preventive care and treatment, as pro-
related to clinical practice that highlight the challenges clinicians face in the routine care of patients with
established mitochondrial disease. Concerning variability in treatment and preventative care approaches were
noted. We hope that sharing this information will be a first step toward formulating a set of consensus criteria
and establishing standards of care.
© 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
As discussed in the first part of this series, the Mitochondrial
Medicine Society (MMS) assessed the current state of clinical practice
including diagnosis, treatment and subsequent preventative care, as
provided by a survey of mitochondrial disease specialists in North
America. Our aim wastodeterminewhether there wassomeconsensus
in regard to how a diagnosis of mitochondrial disease is made and how
clinical care is provided. We hope that by obtainingthis information we
can begin moving towards formulating a set of consensus criteria and
establishing optimal standards of care.
In thefirst paper(Parikhetal.,in press) we discussedthe challenges
that the path taken to establish a diagnosis of a mitochondrial disease
and the eventual diagnosis given varied between providers. Diagnostic
algorithms are limited by the lack of sensitive and specific disease bio-
markers and a reliance on invasive biochemical testing in skeletal
In parallel with the lack of consensus regarding the diagnostic
evaluation, there are no consensus or otherwise widely accepted
practice parameters that clinicians can utilize for patient manage-
ment. A lack of understanding of the natural history of the multi-
tudes of mitochondrial diseases exacerbates this dilemma. Most
mitochondrial medicine providers have cobbled together an infor-
mal set of rules and paradigms for monitoring, preventive care and
management based on published evidence combined with anecdotal
experience and theoretical concepts. How appropriate and necessary
these evaluations and interventions are remains unclear because of
the limitations of the available data.
Despite the relatively high prevalence of mitochondrial disease
there still are no FDA-approved mitochondrial-specific therapies. The
first novel compound (EPI-743) to treat mitochondrial disease has just
entered clinical trials in the recent past. Most mitochondrial-specific
therapies depend upon compounds not regulated by the FDA. Only
a few select studies of these vitamins and xenobiotics prior to 2012
were deemed acceptable by the Cochrane Collaborative and even
fewer individual treatments have shown efficacy. (Pfeffer et al.,
In this second of two papers, we report on the challenges clinicians
face in the routine care of patients with established mitochondrial
disease. Information was obtained through a series of surveys of mito-
cluding vitamin and xenobiotic use for acute, chronic and preventative
care; monitoring including periodic lab work and testing; and manage-
ment of patients during metabolic stressors such as surgery, illness and
do not review the basics of treating mitochondrial disease. For those
readers that wish to familiarize themselves with the principles that un-
derlie mitochondrial disease treatment practices, we direct the readers
The methods on how the surveys were obtained were reviewed in
sicians who direct a mitochondrial disease clinic were recruited via an
open invitation to participate in ten surveys constructed by the MMS.
All ten surveys were constructed and completed between July through
December, 2012. Results were tabulated manually and reported.
Physiciandemographics, clinic structure and organization,and diag-
nostic challenges were reviewed in the first half of this series.
3. Results and discussion
3.1. Vitamin and xenobiotic use (Table 1)
Pharmacologic doses of vitamins and xenobiotics represent a current
mainstay of mitochondrial treatment though the evidence base for their
use is generally limited. Review of the individual compounds and ratio-
nale behind their use is available elsewhere and will not be reviewed
here. (Parikh et al., 2009) A list of compounds commonly used is shown
in Table 1. The most commonly prescribed ones are coenzyme Q10
(CoQ10), Levo-carnitine (L-carnitine), L-arginine and creatine. L-arginine
is universally used for patients during a metabolic stroke. Most clinicians
also use daily oral L-arginine supplementation as a preventative measure
in their patients with a history of metabolic strokes (though two physi-
cians limit its use to patients with MELAS syndrome).
3.1.1. Vitamin combinations
When starting vitamins, some physicians begin one-at-a-time while
others begin many together. The group was evenly split in this regard.
Rationale given for starting one compound at a time included patient
history (especially if a patient has gastrointestinal symptoms), previous
toleranceissues,and minimizingordelineatingside effectsand efficacy.
Rationale for a cocktail approach from the beginning included the
medications having a synergistic effect when used together.
to six compounds at a time. Most vitamin combinations were reported
by a single clinician each, thus demonstrating what has often been
speculated: that the “mitochondrial cocktail” is not uniform and varies
for efficacy, with carefully selected outcome measures to assess
benefits in this heterogeneous group of patients with mitochondrial
If more than three vitamins are utilized at a time, almost all physi-
cians stated that they use a compounding pharmacy. In some cases,
an attractive option for patients on multiple vitamins. Two physicians
stated that they actively avoid a compounding pharmacy, one of them
citing recent concerns of medication contamination and that these
companies are not regulated.
S. Parikh et al. / Mitochondrion 13 (2013) 681–687
3.1.2. Treatment efficacy
One of the most difficult issues with using vitamins, either singly
or as a “cocktail” is the issue of assessing efficacy. A lack of reliable
biomarkers to follow these diseases and therapeutic efficacy is
problematic. There are no biochemical markers to date or other
clear measurement tools that are helpful in all cases to determine
Mostproviders donot checkvitamin levels.If checked, some aim for
levels above the reference range. Treatment efficacy might also be
assessed via subjective measures including patient or parental reports
of energy levels or exercise tolerance, therapist or teacher reports,
measures used include following the Newcastle quality of life scale,
using a timed walk or stair climb test, using formal exercise physiology
testing measuring maximal oxygen uptake and anaerobic threshold or
periodically testing neuropsychological function.
Almostall cliniciansfelt that a clinically significantresponse to these
vitamins by itself did not necessarily make it more likely that a patient
had primary mitochondrial disease.
Few recommend a specific manufacturer for their vitamins. CoQ10
and creatine were the two compounds where a specific manufacturer
was sometimes recommended, though the range of companies used
by providers varied notably.
3.1.4. Adverse effects
Side effects from vitamins reported to providers by their patients
include those from carnitine (diarrhea, fishy odor, and increased
fatigue), CoQ10 (hyperactivity, insomnia, and rash), riboflavin (nausea
and vomiting), and folinic acid (increased self-stimulatory behaviors).
Treatments were generally considered to be well tolerated.
3.1.5. Insurance coverage
Insurance coverage of these compounds varied significantly be-
tween providers and the states they practiced in. Carnitine was often
covered. Folinic acid, L-arginine and CoQ10 were covered for some pro-
viders. Most physicians stated that using a compounding pharmacy
allowed for insurance coverage of non-prescription vitamins at times.
For some, use of a compounding pharmacy led to a loss of insurance
3.2. Preventative care (Table 2)
The role of exercise in patients with mitochondrial disease is being
studied with some evidence that exercise leads to improvements in
Preventative care patterns.
N out of 32
Exercise therapy recommended
Consultation with trainer or therapist
Land-based aerobic activity
(walking, running, bicycle)
Water-based aerobic activity
(pool therapy, swimming)
Resistance training (free weights)
Need to monitor aerobic tolerance
Via consultation with cardiology, pulmonology
and/or cardiopulmonary exercise testing
(treadmill/bicycle stress or walk test)
Type of diet recommended:
Small frequent meals and limited fasting
Lower fat and carbohydrate diet
Varied depending on patient metabolic profile
Need for a dietitian
Selectively if concerns about weight or
Periodic lab work in asymptomatic patients
Every 6 months
Every 1–2 years
Pattern of vitamin and xenobiotic use among providers.
N out of 32
Compounds used most often
L-Arginine for metabolic strokes
CoQ10 as ubiquinol or ubiquinone
Use of vitamin combinations (“cocktail”) at start of therapy?
Vitamin combinations used most often
Unique combination reported by single physician
Carnitine + CoQ10
Carnitine + CoQ10 + B-complex
Number of compounds most often used per patient
No preference or need more data
Use of a specific formulation/manufacturer
Measurement of CoQ10 levels
Goal level 2–4× normal range
Goal level just above normal range
Leukocyte levels preferred
Plasma levels preferred
IV during an acute stroke
For as long as patient is symptomatic
Daily use, oral, for stroke prevention
Monitoring of L-arginine levels
Pre- and post-treatment
Use of compounding pharmacy
Dosing of vitamins
Dose based on reaching level above reference
Dose based on clinical reports of symptom
Response to vitamins suggests diagnosis of primary mitochondrial disease?
Insurance coverage for vitamins
S. Parikh et al. / Mitochondrion 13 (2013) 681–687
mitochondrial function and heteroplasmy shifting in favor of healthy
mitochondrial DNA. (Jeppesen et al., 2006; Taivassalo and Haller,
2005; Tarnopolsky, 2009) Most of our surveyed physicians recommend
an exercise regimen for their patients along with consulting a trainer or
therapist. The individual exercise regimen and monitoring of exercise
tolerance varied a great deal.
3.2.2. Diet & nutrition
Little research exists on dietary therapy for mitochondrial disease.
Thus it is not surprising that recommendations vary significantly be-
tween providers. The use of a dietitian also varied between providers.
3.2.3. Lab work
Most physicians obtain some screening laboratory work in
otherwise asymptomatic already diagnosed patients. Most obtain
testing every 1–2 years and a few tests every 6 months. Tests sent
vary between providers and the ones obtained most commonly
are shown in Fig. 1. These most often include periodic screening
for liver and thyroid dysfunction, diabetes and renal tubular acidosis/
3.3. Preventative studies
The pattern of other preventative studies obtained commonly by
various providers is shown in Fig. 2. Further details are noted below
and the tests or interventions are listed in the frequency with which
they are obtained.
3.3.1. Cardiac consultation
Cardiac consultation and monitoring are obtained most often,
including testing via EKG and echocardiograms with timing varying
between 6 months to 2 years. Most physicians agree that patients at
higher risk for arrhythmias (Kearns-Sayre syndrome, for example)
need more frequent monitoring. Almost all physicians clarified that
of cardiomyopathy, studies are obtained more frequently.
or if the cardiologist recommended it and typically only repeated at the
cardiologists' discretion. Exercise physiology stress tests are mostly ob-
tained at the cardiologists' discretion. Exceptions include patients with
Fig. 1. Preventative lab work obtained.
Fig. 2. Preventative testing obtained.
S. Parikh et al. / Mitochondrion 13 (2013) 681–687
severe fatigue and exercise intolerance where quantifying maximal
oxygen consumption (VO2 max), maximal workload, and anaerobic
threshold may help. Cardiac magnetic resonance imaging is not routinely
obtained in patients without active cardiac disease.
3.3.2. Ophthalmology evaluations
Ophthalmology evaluations are the next most common recommen-
dation in otherwise stable or asymptomatic patients. Most providers do
optical coherence tomography in asymptomatic patients unless recom-
mended by an ophthalmologist.
Audiograms are typically obtained in asymptomatic patients by
many clinicians though the frequency of testing varies.
3.3.4. Sleep studies
Sleep studies are not automatically obtained by all to evaluate day-
time fatigue. While almost half of the providers obtain them routinely,
the remainder only obtain sleep studies if there are other risk factors
for sleep apnea.
3.3.5. Immunologic studies
Immunologic studies are not routinely assessed in mitochondrial
patients. Some providers do obtain testing, but only if the patient has
a history of frequent infections. When an immunologic evaluation is
started by the mitochondrial specialist, all (12/12) obtain a complete
blood count, most (67%; 8/12) obtain immunoglobulin levels, 33%
(4/12) assess antibody response to vaccinations and 25% (3/12) assess
B- and/or T-cell function.
Neuroimaging is not typically repeated in otherwise stable patients.
A small group stated that they might repeat imaging depending on the
characteristics of the underlying disease (evaluating white matter in a
patient with white matter disease or for basal ganglia and brainstem
health in a patient with Leigh syndrome for example).
3.3.7. Spinal fluid collection
Spinal fluid collection is not typically repeated in otherwise stable
patients; a few providers repeat lumbar punctures in stable patients,
typically to follow cerebral 5-methyltetrahydrofolate levels.
3.3.8. Resting metabolic rate
Resting metabolic rate assessed via indirect calorimetry, is not typi-
cally assessed. Many cited concerns including variable results despite
using a fixed protocol, difficulty with test completion for some patients
and that it may not be an accurate reflection of mitochondrial function.
3.3.9. Gastrointestinal (GI) studies
Gastrointestinal (GI) studies including evaluation of swallow and
motility in otherwise asymptomatic patients, are typically obtained at
thegastroenterologists discretion. A third ofsurveyed physicians obtain
this testing on their own in patients at high-risk for developing
dysphagia or dysmotility. The majority will defer motility testing to
Dysautonomia when suspected, is evaluated by consulting with a
Preventative IV fluid therapy when a patient is well is not recom-
mended by most with some stating that there is a lack of evidence-base
or physiologic rationale for this type of treatment. Some have used such
treatment selectively, though specific instances of situations in which
they choose to begin such therapy were not provided.
3.4. Management during periods of catabolic stress
Clinical manifestations of many metabolic disorders including mito-
chondrial diseases are worsened during times of catabolic stress, often
anesthetics or surgery. Certain preventive maneuvers are utilized in the
hopes of staving off medical or neurologic deterioration during these
periods. These measures, including limiting fasting and utilization of
intravenous glucose to stop catabolism, have shown benefit for tradi-
tional inborn errors of metabolism and their use has been extrapolated
to mitochondrial patients.
3.4.1. Hydration with illness
hydration during times of illness though provider opinion varied as to
whether only those patients at risk of dehydration should be admitted.
The type of IV fluid provided and use of IV carnitine was inconsistent as
well. Use of an emergency precautions letter was common.
3.4.2. Medication avoidance
Manyrecommend avoidingselect antibioticsduringtimesof illness;
the antibiotics that are avoided vary significantly from physician to
physician. The rationale for antibiotic avoidance for some physicians is
likely due to the concern that mitochondria,having a prokaryotic origin
and structural similarities to bacteria, remain vulnerable to influences
of medications that impair bacterial transcription. The inherent risk of
hearing loss with exposure to aminoglycosides in patients with select
mtDNA mutations is also likely considered. (Pandya, 1993).
Valproic acid (VPA) is noted to have mitochondrial toxicity via a
variety of mechanisms, especially in patients with Alpers–Huttenlocher
syndrome, but also when mtDNA depletion is present. (Saneto et al.,
2010; Silva et al., 2008; Wolf et al., 2008) Most recommend avoidance
of VPA whenever possible as well as sequencing select nuclear genes
for mtDNA depletion prior to initiating valproic acid therapy in an epi-
lepsy patient without an etiologic diagnosis.
Physicians are at times concerned that additional lactate provided
directly through an intravenous line in the form of Ringer's lactate
could precipitate an acute acidotic state or at least perceive to worsen
the lactic acidosis in a patient. One respondent states that the amount
of change in lactate is minor and can be sorted out by obtaining an
arterial blood gas. There is evidence to suggest that lactate levels do
not increase after infusion with Ringer's lactate, especially without
concomitant liver dysfunction. (Didwania et al., 1997; Shin et al., 2011).
3.4.3. Anesthesia precautions
Anesthesia related concerns in mitochondrial disease patients exist
since most anesthetic agents impair mitochondrial function in vitro.
(Morgan et al., 2002; Zhang et al., 2012) While individuals have looked
at rates of anesthetic complications in mitochondrial patients, the stud-
classified, with most reported patients not having a genetically con-
firmed diagnosis. (Driessen et al., 2007; Finsterer et al., 2005; Footitt
et al., 2008; Shear and Tobias, 2004).
All physicians surveyed recommend anesthesia precautions in
patients with suspected or diagnosed mitochondrial disease. The
specific recommendations vary but generally involve restricting select
anesthetic agents, limiting pre- and post-operative fasting, maintaining
IV hydration with dextrose, consideration of a bispectral index (BIS-)
monitor when using inhaled agents and involving an anesthesiologist
as a consultant well before the surgery. Use of an anesthesia protocol
letter was common. The specific list of anesthetic agents avoided varied
thoughconcernswere often raised about propofol (Finstererand Segall,
2002) There are reports of these agents being tolerated by mitochondrial
patients as well. (Driessen et al., 2007; Footitt et al., 2008).
S. Parikh et al. / Mitochondrion 13 (2013) 681–687
3.4.4. Surgical precautions
When scheduled for surgery under general anesthesia patients
are often instructed to fast for several hours prior to their procedure.
Theoretically, fasting leads to catabolism and this may predispose
mitochondrial patients to enter a surgical procedure (another catabolic
event with a highrelease of stress hormones) in a metabolically vulner-
able state. Slightly over half of the physicians admit all mitochondrial
patients prior to surgery for intravenous dextrose during the fasting
state. The remainder admit patients preoperatively for hydration if
the patient has had a problem in the past with fasting, anesthesia, or
3.4.5. Vaccination in mitochondrial disease
18.104.22.168. All respondents recommend their patients receive all standard
are shown in Table 3.
3.5. Education & support
Clinicians were asked about their involvement or consultation
with patient support groups, how they educate patients, families and
physicians about mitochondrial disease, as well as their participation
in advocacy efforts. These findings are detailed in Table 4.
3.5.1. Support groups
The United Mitochondrial Disease Foundation and MitoAction
groups were the two support groups with which most physicians
interacted. Local support groups were mentioned as well. Physician
roles included giving educational talks to families or physicians, serving
are not compensated for their work with these support groups as it is
performed on a voluntary basis. However, when travel is involved, it
may be sponsored in some way by the organization or via proxy with
unrestricted educational grants from corporations or through hospital
3.5.2. Patient and physician education
Clinicians typically provided patient education during the office
cians or their own medical centers or a national support organization.
Providers agreed that there is a need to create a shared repository of
educational materials online to assist in educating patients.
Most surveyed physicians are actively involved in educating physi-
cians and trainees about mitochondrial disease in their local region
while many are also involved speaking at a national level.
Advocacy at a local and national level was espoused with both
the medical organizations and support groups playing critical roles. A
comment of note included, “We are a poorly funded, underserved com-
munity and without advocacy and awareness it will only worsen over
time. I was not in favor of this initially but see there is value. If we do
not, who will? It provides credibility. Physicians should be advocates
for all of their patients where feasible. Misconceptions abound. We
know the problems our families face.”
The practice of mitochondrial medicine is relatively young and
clinicians currently have little formal guidance in regard to providing
patients with optimal care. The MMS surveyed a group of physicians
specializing in mitochondrial disease from across North America,
Physician roles in support groups, patient education and advocacy.
N out of 32
Participation with at least one family support group
Participation with more than one support group
Specific groups mentioned and utilized
United Mitochondrial Disease Foundation
Both of the above
(Groups mentioned by b2 physicians not included)
Physician's role in support groups
Educational resource to families
Educational resource to physicians
Directly during the office consultation
Use of educational materials developed by support groups
Use of self-developed educational materials
Need for a shared repository for patient education
Need for patient education prior to appointment
Via online documents
Via online video
Via online slide show
Providing lectures to local physician or student community
Providing lectures to national physician community
Providing lectures to allied health professionals
Needed at government level
Organized thru medical society
Organized thru family support group
Management during periods of catabolic stress.
N out of 32
Hospital admission for IV dextrose
Only when oral intake has decreased or vomiting
With any illness (for select patients depending on
Fluid type used
Use of D5 IV fluids
Use of D10 IV fluids
Depends on patient lab work
Use of supplemental carnitine in fluids
Carnitine dose increased from home dose
Use of additional supplements when ill
Use of an emergency protocol letter
Medication and fluid avoidance
Select antibiotics (list varied between providers)
Valproic acid (regardless of mitochondrial disease type)
Sequencing of POLG1 prior to beginning valproate in
patients with epilepsy and no clear diagnosis
Use of an anesthesia protocol letter
Restricted to short procedures (less than 2 h)
Avoid if possible
Succinylcholine avoidance due to concerns of
Admission for IV fluids preoperatively
Admission only if prior history of adverse response
Restricting vaccinations to times of good health
Pre-medication with anti-inflammatories or anti-oxidants
Alter schedule to provide fewer immunizations at one time
S. Parikh et al. / Mitochondrion 13 (2013) 681–687
spanning 17 states and parts of Canada, to assess the current state
of clinical mitochondrial practice. This is the second of two papers
reporting our results.
The practiceof mitochondrial medicineamongthe respondents is in
showed that clinic structures and organization, along with physician
aligned in our cohort. Similarities exist in diagnostic approaches used.
Notable differences in the interpretation of results leads to a lack of
consensus on whether or not a diagnosis of mitochondrial disease is
This second part of our series shows that there is also variability in
treatment and preventative care approaches. While most physicians
recommend the use of vitamins and xenobiotics, the actual regimen
used differs considerably between providers. Further randomized,
double-blinded trials to assess their efficacy are needed though the
wide variability in etiology and natural history of the many mitochon-
drial disorders has posed a challenge. Select preventative screening for
multi-system involvement was routine as was the care recommended
during times of catabolic stress.
This report highlights a critical need for diagnostic testing, chronic
in thefield. The Mitochondrial MedicineSociety plans to embark on de-
Didwania, A., Miller, J., Kassel, D., Jackson Jr., E.V., Chernow, B., 1997. Effect of intravenous
lactated ringer's solution infusion on the circulating lactate concentration: part 3.
Results of a prospective, randomized, double-blind, placebo-controlled trial. Crit.
Care Med. 25, 1851–1854.
Driessen, J., Willems, S., Dercksen, S., Giele, J., van der Staak, F., Smeitink, J., 2007.
Anesthesia-related morbidity and mortality after surgery for muscle biopsy in chil-
dren with mitochondrial defects. Paediatr. Anaesth. 17, 16–21.
Finsterer, J., Segall, L., 2010. Drugs interfering with mitochondrial disorders. Drug Chem.
Toxicol. 33, 138–151.
Finsterer, J., Haberler, C., Schmiedel, J., 2005. Deterioration of Kearns–Sayre syndrome
following articaine administration for local anesthesia. Clin. Neuropharmacol. 28,
Footitt, E.J., Sinha, M.D., Raiman, J.A., Dhawan, A., Moganasundram, S., Champion, M.P.,
2008. Mitochondrial disorders and general anaesthesia: a case series and review.
Br. J. Anaesth. 100, 436–441.
Jeppesen, T.D., Schwartz, M., Olsen, D.B., Wibrand, F., Krag, T., Duno, M., Hauerslev, S.,
Vissing, J., 2006. Aerobic training is safe and improves exercise capacity in patients
with mitochondrial myopathy. Brain 129, 3402–3412.
Morgan, P.G., Hoppel, C.L., Sedensky, M.M., 2002. Mitochondrial defects and anesthetic
sensitivity. Anesthesiology 96, 1268–1270.
Pandya, A., 1993. Nonsyndromic hearing loss and deafness, mitochondrial. In: Pagon, R.A.,
Bird, T.D., Dolan, C.R., Stephens, K., Adam, M.P. (Eds.), Genereviews. University of
Washington, Seattle, Seattle (WA).
Parikh, S., Saneto, R., Falk, M.J., Anselm, I., Cohen, B.H., Haas, R., Medicine Society T.M.,
2009. A modern approach to the treatment of mitochondrial disease. Curr. Treat.
Options. Neurol. 11, 414–430.
Parikh, S., Goldstein, A., Koenig, M.K., Scaglia, F., Enns, G.M., Saneto, R., Mitochondrial
Medicine Society Clinical Directors Working Group, in press. Practice patterns of
mitochondrial disease physicians in North America. Part 1: diagnostic and clinical
challenges. Mitochondrion. http://dx.doi.org/10.1016/j.mito.2013.07.116.
Pfeffer, G., Majamaa, K., Turnbull, D.M., Thorburn, D., Chinnery, P.F., 2012. Treatment for
mitochondrial disorders. Cochrane Database Syst. Rev. 4 (CD004426).
Saneto, R.P., Lee, I.C., Koenig, M.K., Bao, X., Weng, S.W., Naviaux, R.K., Wong, L.J., 2010.
POLG DNA testing as an emerging standard of care before instituting valproic acid
therapy for pediatric seizure disorders Seizure.
Shear, T., Tobias, J.D., 2004. Anesthetic implications of Leigh's syndrome. Paediatr.
Anaesth. 14, 792–797.
Shin, W.J., Kim, Y.K., Bang, J.Y., Cho, S.K., Han, S.M., Hwang, G.S., 2011. Lactate and liver
function tests after living donor right hepatectomy: a comparison of solutions with
and without lactate. Acta Anaesthesiol. Scand. 55, 558–564.
Silva, M.F., Aires, C.C., Luis, P.B., Ruiter, J.P., Ijlst, L., Duran, M., Wanders, R.J., Tavares de
Almeida, I., 2008. Valproic acid metabolism and its effects on mitochondrial fatty
acid oxidation: a review. J. Inherit. Metab. Dis. 31, 205–216.
Taivassalo, T., Haller, R.G., 2005. Exercise and training in mitochondrial myopathies. Med.
Sci. Sports Exerc. 37, 2094–2101.
Tarnopolsky, M.A., 2009. Mitochondrial DNA shifting in older adults following resistance
exercise training. Appl. Physiol. Nutr. Metab. 34, 348–354.
Wolf, N.I., Rahman, S., Schmitt, B., Taanman, J.W., Duncan, A.J., Harting, I., Wohlrab, G.,
Ebinger, F., Rating, D., Bast, T., 2008. Status epilepticus in children with Alpers' disease
caused by POLG1 mutations: EEG and MRI features. Epilepsia 50, 1596–1607.
Zhang, Y., Xu, Z., Wang, H., Dong, Y., Shi, H.N., Culley, D.J., Crosby, G., Marcantonio, E.R.,
Tanzi, R.E., Xie, Z., 2012. Anesthetics isoflurane and desflurane differently affect
mitochondrial function, learning, and memory. Ann. Neurol. 71, 687–698.
S. Parikh et al. / Mitochondrion 13 (2013) 681–687