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Reigning in Charley’s
Horses
Muscle cramps in Neuromuscular
Disease
Dr. Hans Katzberg MD Msc FRCPC
Assistant Professor of Medicine, University of Toronto
Prosserman Centre for Neuromuscular Diseases
Toronto General Hospital
Objectives
 1) To define muscle cramps and be able to distinguish them from
other hyperexcitable neurological phenomena
 2) To review the pathophysiology and electrophysiology
underlying the development of neurogenic muscle cramps
 3) To understand current management strategies in the care of
patients with neurogenic muscle cramps
 4) To describe current and novel methods of assessing muscle
cramps clinically and in clinical research
Outline
 What is a muscle cramp?
 Electrophysiology and pathophysiology
 Cramps across the spectrum of disease and health
 Treatment of muscle cramps
 Guidelines (AAN, Cochrane)
 Clinical practice
 Research
 Outcome measures
Disclosures
 I serve as a consultant and participate in clinical
research studies for Flexpharma (treatments for
muscle cramps), IVIG companies Octapharma, CSL
Behring, Grifols and for Sanofi-Genzyme
 I am hold a grant from the University of Toronto for the
development of a clinical cramp index for muscle
cramps
Origins
“Charley Horse”
Origins
“Charley Horse”
A lame horse named Charley pulled the
roller on the Chicago White Sox ballpark in
the 1890s.
Boston Globe, 17 July 1886: Joe Quest,
said to have experienced “charlie horse”
The pitcher Charley Radbourne (Boston)
was nicknamed Old Hoss. He got cramp
during a baseball game in the 1880s.
Origins
“Charley Horse”
“Choppers”or “Corky”
Terminology England : “dead leg”,
“granddaddy”, “chopper”
Terminology Australia: “corked thigh” or
"corky”
Link with US terminology?


Policemen in 17th century England were
supposed to be called Charleys and the
term migrated to America.
The amount of walking the police were
required to do gave them aching legs.
Definition : Muscle Cramps
•
Acutely painful, explosive onset, resulting in
visible, palpable contraction in one muscle or part
of a muscle, with persistent soreness
•
Associate with trivial movements or forceful
contraction (especially in already shortened
muscle)
•
Stretching the muscle usually terminates cramp
•
A neurogenic cramp has a specific needle
electromyographic signature, namely high
frequency (50-150 Hz) continuous discharges,
which distinguishes it from other hyperexcitable
muscle conditions
Miller et al. Muscle Nerve 2005.
Men’s Health June 2015
Cramp Discharges on EMG
Evaluation of Cramp Potentials
•
~50 motor units were identified from the
intramuscular EMG recordings.
•
The average discharge rate over the interval
of activity was 14.5 Hz.
•
A relatively small proportion of motor units
(6/48) had peak rates >30 Hz.
• Bursts of 150 stimuli at frequencies
increasing from 4 Hz at increments of 2 Hz
until the cramp was elicited.
•
•
•
•
The presence of a cramp was assessed by
1) subject feedback
2) clinical observation
3) presence of involuntary EMG activity
Minetto et al. J Neurophysiology 2009.
What is NOT a muscle cramp?
EMG may be useful to
identify hyperexcitable
neurological phenomena
Cramps may co-exist with
other neuropathic findings
or phenomena
Outside the experimental
setting, it is not routine to
elicit muscle cramps during
assessment
Katzberg HD. Journal of Neurology 2015
Muscle Cramps: Pathophysiology
Image courtesy of Kimberly Chin
Katzberg HD. Journal of Neurology 2015
Prevalence of Muscle Cramps
 Muscle cramp are uncommon in children under age eight
Leung AK et al. JAMA. 1999; 91(6):329–32
 Muscle cramps appear to be common in adolescents / young adults
 In a survey of 121 college students:
 115 had experienced at least one muscle cramp
 18 had been awoken from sleep more than twice a month with muscle cramps.
Norris FH. Electro Neurophysiol 1957;9:139-47.
 Cramps can become more of a problem in older ages
 A cross-sectional prevalence study of 365 outpatients aged 65 or older in the UK reports
that 50% of outpatients report frequent cramps2.
Abdulla AJ. Int J Clin Pract. 1999; 53:494–496.
Garrison et al. CMAJ 2015
Causes of Neurogenic Muscle Cramps


Physiological

No underlying condition (IDIOPATHIC)

Uremia

Nocturnal leg cramps in elderly

Cirrhosis

Exercise related cramps

Hypothyroidism

Pregnancy


•
Metabolic disorders
Lower motor neuron disorders
•
ALS
•
Polio/post-polio
•
Radiculopathy
•
Neuropathy
PNS

Acute extracellular volume depletion

Perspiration (“heat cramps”)

Hemodialysis

Diarrhea, vomiting
Medications

Long acting B2 agonists

Thiazide(like) diuretics
Neurological conditions

K+ sparing diuretics
•
Parkinson’s Disease

Loop diuretics
•
Multiple Sclerosis

Statins
•
Stroke
CNS
Garrison et al. Arch Int Med 2012
Cirrhosis / Hemodialysis
 Cirrosis:

May be caused by the reduction of the
effective circulating volume

Weekly infusion of human albumin may
be an effective treatment
 Hemodialysis:

Changes in plasma osmolality and/or
extracellular fluid volume have been
implicated

Occurs in 33 to 86 percent of patients

Often result in the early termination of a
hemodialysis and therefore a significant
cause of underdialysis
Hepatology 1996 Feb;23(2):264-73
Adv Chronic Kidney Dis 2011. Nov;18(6):428-32
Cramps in Pregnancy
Young G. BMJ Clinical Evidence 2009.
Causes of Neurogenic Muscle Cramps
Table 1. Proportion of physicians reporting the occurrence of each cause for muscle cramps as
well as the common causes.
Underlying Cause
Neurological Conditions
Idiopathic
Physiological
Pregnancy Related
Medication Related
Medical Conditions
†
Other
Percent
Most
Observed
(N=51)
45.0
41.7
8.3
5.0
3.3
0.0
0.0
Percent
Ever
Observed
(N=51)*
80.4
84.3
58.8
15.7
47.1
52.9
3.9
Specific Cause
Percent
Most
Observed
Percent
Ever
Observed*
Medical Conditions
Uremia
Hemodialysis Related
‡
Other
Thyroid Dysfunction
Cirrhosis
Neurological Conditions
N=30
28.6
22.9
22.9
17.1
5.7
N=45
N=29
72.4
62.1
41.4
62.1
31.0
N=43
Neuropathy
§
Other
Radiculopathy
ALS
Cramp-Fasciculation
Syndrome
35.8
22.6
18.9
13.2
9.4
88.4
44.2
72.1
72.1
53.5
*
Percent numbers do not add up to 100 due to multiple responses.
Metabolic myopathies and other metabolic disorders.
‡
Anemia, apnea, root lesions, and electrolyte disturbance.
§
Restlessness, myopic disorders, mitchondriac diseases, muscular dystrophies and MS.
†
Lim Fat and Katzberg J Ank Foot Res 2012.
Prevalence of Cramps in Diabetes
 242 patients with diabetic neuropathy enrolled in a trial with Epalrestat or
Methylcobalamine had a rate of muscle cramps of 76.5–78.2% at baseline1
T1D (N=46)
T2D (N=67)
Control (N=36)
50.0*
79.1***
27.9
T1D (n=23)
T2D (n=53)
Control (n=10)
Frequency (per month)
3.0 (0-10)
9.9 (0-60)
1.5 (0-5)
Duration (min)
2.1 (0-10)
7.8 (0-90)
7.3 (1-20)
Severity (/10)
5.5 (0-10)
6.6 (0-10) **
3.5 (1-7)
8.7
31.4
10.0
95.7
100
100
Cramp Experience (Y) %
Of those who have MC
Disabling (% Y)
Lower Limbs (% Y)
p = 0.0399
p =0.0011
*** p < 0.0001
*
**
1 Maladkar
2
et al. Int J Diabetes Dev Ctries. 2009.
Maxwell S, Kokokyi S, Lovblom E, Perkins B, Bril V, Katzberg H. Diabetes Care 2009.
•
Muscle cramps are a common and frequently disabling symptom, which may
affect physical quality of life in patients with polyneuropathy.
•
Equal prevalence and characteristics of muscle cramps across different types
of neuropathies, including small fiber neuropathy
Neuromuscular Disorders 2014
• 12 patients with muscle cramps and without symptoms of neuropathy
underwent skin punch biopsy
• Intraepidermal nerve fiber density reduced in 7 patients, only 1 identified to
have cause for neuropathy
Muscle Nerve 2013
Voltage Gated K+
Channelopathy
Cramp Fasciculation Syndrome




Patients with muscle aching, cramps, stiffness,
exercise intolerance, and peripheral nerve
hyperexcitability
Neurologic examination showed calf fasciculations,
quadriceps and deltoid myokymia
Nerve stimulation at 0.5, 1,2, and 5 Hz produced
showers of electrical potentials following the M
response

Cramps, stiffness, fasciculations, myokymia
can accompany neuromyotonia;
afterdischarges and continuous motor
activity on EMG

Associated myasthenia gravis or thymoma,
and rarely lung cancer

Can be associated with voltage gated
potassium channel antibodies (LGI1 and
CASPR)

If associated with central nervous system
pathology, can be related to Isaac’s
Syndrome
Carbamazepine therapy caused moderate-to-marked
reduction of symptoms and nerve hyperexcitability.
Tahmoush et al. Neurology 1991 41:1021.
Neurol Clinics. 2010; 28(4):941-59.
Cramp after discharges
Figure 1. (A) Normal Study. (B) After-discharges. (C) Cramp
Potential. (D) Continuous Motor Unit Activity.
Familial Cramps
 No specific genetic target has been implicated in
patients with muscle cramps
 Based on selected families identified with muscle
cramps, there may be a hereditary component
 Most families reported to have an autosomal dominant
inherited pattern
Jacobsen JH et al. Sleep. 1986; 9:54–60.
 At TGH, 3 identified families with autosomal dominant
inherited pattern prominent muscle cramps with a total
of 10 affected people
Investigations
Investigations not required if
cramps are:
•
•
Situational (after exercise)
Infrequent
Slow RNS even at 5 Hz may
be normal, especially if
cramps are infrequent
VGKC not routinely tested,
only if suspicion of
neuromyotonia or Isaac’s
syndrome
Katzberg HD. Journal of Neurology 2015
Quinine Sulphate
 Quinine and derivative used to treat muscle
cramps since uncontrolled studies in the
1940s
 Inc refractory period, reducing response to
repetitive stimulation
 Reduces motor end plate excitability 
diminished response to nerve stimulation /
Ach
•
“Due to continued reports of serious side effects patients using
Qualaquin "off-label” for night time leg cramps, the U.S. Food and
Drug Administration (FDA) has approved a risk management plan
to warn against use for such unapproved uses. Qualaquin should
not be used for night time leg cramps.”
Harvey 1939, Gootnick 1943; Moss 1940; Nicholson 1945.
• 563 articles identified if prospective clinical trial with effect on muscle
cramps as a primary or secondary outcome (18 randomized tx trials)
• 2 Class I studies showed modest benefit of efficacy of quinine
derivatives
• “Although likely effective (Level A), quinine derivatives should be
avoided for routine use in the management of muscle cramps
because of the potential of toxicity, but in select patients they can
be considered for an individual therapeutic trial once potential side
effects are taken into account.”
Katzberg H, Kahn A, So YT. Neurology 2010.
• There is one Class II study each to support the use of:
• Vitamin B complex
• Naftidrofuryl
• Calcium channel blockers (diltiezam, verapamil)
• Intramuscular lidocaine
• These Rx are possibly effective and may be considered in management of
muscle cramps (Level C)
• No clinical trials have systematically evaluated antiepileptics such as
carbemazepine or dilantin or anti-spasmodics such as baclofen for
treatment of muscle cramps
Katzberg H, Kahn A, So YT. Neurology 2010.
Cramps in ALS (Cochrane)
 Twenty studies including 4789 participants were identified.
 Vitamin E, baclofen, riluzole, L-threonine, xaliproden, indinavir,
and memantine (13 trials, 20 outcome)
No Effect
 One trial of tetrahydrocannabinol (THC) as 10 endpoint.
 Creatine, gabapentin, dextromethorphan, quinidine, and lithium (6
studies as adverse event)
 Authors' conclusions No evidence to support use of any
intervention for muscle cramps in ALS/MND. More / larger
randomised controlled trials evaluating treatments for muscle cramps
in ALS/MND are needed.
Balinger R, Katzberg H, Weber M.
Cochrane Syst Database Rev.
2012 Apr 18;4:CD004157.
Mexilitine for Cramps
 2 small studies in idiopathic muscle cramps (14 patients) and Machado
Joseph Syndrome (20 patients) showed possible benefit of the drug
over placebo
Kanai, et al. Brain 2003
 Mexilitine had significant effects on cramp frequency (31% of placebo 300
mg, 16% of placebo 900 mg) and cramp intensity (45% of placebo 300
mg, 25% of placebo 900 mg)
 Higher rate of discontinuation due to adverse events at 900 mg dose
Weiss, et al. Neurology Feb 2016.
Practice Patterns in the Treatment of
Muscle Cramps in Ontario
Table 5. Proportion of physicians who use each modality of treatment and non-pharmacological
agents, and percentage of physicans who most frequently use each of the aforementioned
factors.
Factor
Treatment Modality
Non-Pharmacological
Pharmacological
Combination of Non-Pharmacological and Pharmacological
Non-Pharmacological Treatment
Stretching
Hydration
Massage Therapy
Other†
Herbal Remedies
*
†
Percent Most
Prescribed
N=52
37.7
32.8
29.5
N=44
50.0
20.0
13.3
8.3
3.3
Percent Ever
Prescribed*
N=51
60.0
64.0
48.0
N=43
81.4
55.8
46.5
20.9
9.3
Percent numbers do not add up to 100 due to multiple responses.
Tonic water, physiotherapy, and physical exercise.
Lim Fat and Katzberg. J Ankle Foot 2011
Practice Patterns in the Treatment of
Muscle Cramps in Ontario
Table 6. Proportion of physicians who use pharmacological treatment, and percentage of those
who most frequently use of these agents, as well as the respective tolerance for each agent.
Pharmacological
Treatment
Baclofen
Quinine and its derivatives
Vitamin B
Vitamin E
Gabapentin
Other†
Diltiazem
Carbamazepine
Levetiracetam
Phenytoin
Oxycarbazepine
Verapamil
*
†
Percent Most
Tolerated* (N=42)
26.2
26.2
21.4
14.3
11.9
7.1
2.4
0.0
0.0
0.0
0.0
0.0
Percent Most
Prescribed (N=41)
27.5
25.5
5.9
3.9
15.7
11.8
2.0
3.9
2.0
3.9
0.0
0.0
Percent Ever
Prescribed (N=37)*
78.4
70.3
24.3
8.1
73.0
29.7
13.5
40.5
10.8
24.3
2.7
8.1
Percent numbers do not add up to 100 due to multiple responses.
Magnesium supplements, tizanidine, pregabalin, clonazepam, diazepam, mexiletin, Cymbalta,
praxipexole, coenxayme Q, and 1-carnitine.
Lim Fat and Katzberg. J Ankle Foot 2011
Practice Patterns Amongst Neuromuscular Clinicians in US
Treatment
of
Muscle
Cramps
Katzberg HD. Journal of
Neurology 2015
Treatment Flowchart
Pregnancy
Neurogenic
Cramps
Hemodialysis
Cirrhosis
Variable Na
profiling
Weekly albumin
infusions
Magnesium
Sulphate (360 mg
or 15 mmol Mg
citrate/ lactate)
Mild
Stretching /
hydration
Vitamin
supplementation
(Vit B /E)
Ca channel
blockers (diltiezam
30 mg / verapamil
120 mg)
Brewer’s yeast
Over the counter
quinine (15 mg
quinine)
Medications, B12,
Lytes, thyroid,
parathyroid
Moderate-severe
Quinine Sulphate
300 mg qhs
Baclofen 10-50mg
od
Clonazepam 0.5-2
mg / day
Mexilitine 300 mg600mg
Gabapentin 3003600 mg od
Crampfasciculation /
VGKC/abn S-RNS
Antiepileptic Rx
Carbemazepine /
Oxcarbazepine
Leveteracitam
Phenytoin
Patient Centred Outcome Research
Institute (PCORI)
 Patient Assisted Intervention for Neuropathy: Comparison of
Treatment in Real Life Situations (PAIN-CONTRoLS)
 Assessment of Prevention, Diagnosis, and Treatment Options
 Using prospective randomized comparative effectiveness adaptive design study
on patients suffering from neuropathic pain
 Bayesian adaptive design used
 Medications evaluated including nortypyline, duloxetine, pregabalin, mexilitine
Research funded through a Patient-Centered Outcomes Research
Institute (PCORI) Award (CER-1306-02496)
P.I. Richard J. Barohn
Patient Centred Outcome Research
Institute (PCORI)
 Pharmacologial interventions for treatment of muscle
cramps: (INFORMEd)
 Assessment of Prevention, Diagnosis, and Treatment Options
 Similar statistical analysis used to PAIN-CONTROLS study
 Collaborators: University of Kansas (Barohn, ), University of Buffalo (N. Silvestri),
University of Toronto (Katzberg)
 Medications planned for study include: mexilitine, oxcarbazepine, quinine
sulphate, baclofen
In preparation : Co-P.I.’s Nick Silverstri / Hans Katzberg
How have cramps traditionally been
measured in cramp trials?
 Cramp frequency has been used most frequently in clinical studies but
may not comprehensively capture the entire cramp experience.
Is the more to the cramp experience
than frequency?
•
Patients seen at the UHN neuromuscular clinic with
cramps were asked about frequency, severity, duration
and location of muscle cramps as well as disability due
to cramps via questionnaire.
25
•
Data from 225 patients showed that all parameters
including pain on a visual analogue scale, duration of
muscle cramps and cramp frequency correlate well
with self-reported disability from muscle cramps
(r>0.6) and factors not thought to matter, such as pain
from cramps, appear to be pseuonormally
distributed
There is currently an urgent need for new therapeutic
option to treat muscle cramps, in addition to reliable
and validated tools to assess the severity and
impact of cramps.
20
Number of Patients
•
15
10
5
0
Cramp Severity (0-10)
Development of Neuromuscular
Outcome Scales at TGH
 Toronto Clinical Neuropathy Score (TCNS and mTCNS)

“All seven clinical scales were determined to be excellent in discriminating between patients with
neuropathy from controls without neuropathy. The strongest discrimination was seen with the
mTCNS. The best sensitivity and specificity for the range of scores obtained, as determined by
using receiver operating characteristic curves, was seen for the mTCNS followed by the TNSc.”
Zilliox et al. J Diabetes and Complications 2015
•
Myasthenia Gravis Impairment Index (MGI2)
•
•
•
Evaluation of electrophysiogical correlates of as well as minimal clinical important differences in
QMGS
Critical analysis of QMGS+MG-composite scales with traditional and Rasch methods
Development of a practical, validated, responsive, reliable, patient-centered index for MG
Barnett et al. Muscle Nerve 2013.
Katzberg HD et al. J Clin Neuromusc Dis 2012.
Barnett C et al. PLoS1
Katzberg HD et al. Muscle Nerve 2014.
Development of a Novel, Patient-centred Cramp Index:
Toronto Clinical Cramp Index (TCCI)
Literature review
Qualitative
data
Previous measures
Preliminary Items
Measurement
Experts
Local Neurologists
DRAFT VERSION 1
Patients: Cognitive interviews PRO items
Survey to Neuromuscular physicians
and nurses
DRAFT VERSION 2
FIELD TESTING, VALIDATION, RELIABILITY AND
RESPONSIVENESS
Cramp Interviews (qualitative data)
• Script developed and used in semistructured interviews to additional
patients with cramps:
• polyneuropathy,
• motor neuron disease
• idiopathic cramps
• pregnancy-induced cramps
• cramps related to cirrhosis and
hemodialysis.
• Development of a cramp index from
the interviews includes:
• item generation and reduction
using a data saturation method
• starts by developing a
conceptual framework of cramp
severity based on qualitative
data of patent experience.
DIAGNOSIS
GENDER
AGE (yrs)
DURATION OF
INTERVIEW
Idiopathic
M
28
27min 10sec
Idiopathic
F
50
41min 12 sec
Diabetes + Liver
Cirrhosis
M
58
25min 15sec
Diabetes
F
70
40min 42sec
ALS
M
55
18min 38sec
Liver Cirrhosis
F
75
47min 25sec
Pregnancy
F
27
16min 40sec
Exercise induced
cramps
M
48
17min 47sec
Chronic Renal
Failure
F
65
10min 19sec
Quotes
 “I might get two hours of sleep a night, some nights I don't sleep at all.
So it certainly affects me during the day, I am more irritable, just not
focused at work”
 “From a dead sleep, I'll just wake up in screaming pain”
 “Muscles are rock solid and I can't move.”
 “It's hideous. It hurts too much to cry.”
 “I can't get into the bathtub, and if I'm in the bathtub, I won't be able to
get out because that's going to entail bending my leg.”
 “I imagine that the pain is AS severe as having a heart attack.”
Grouped Codes (samples)
Duration
Location
Bad cramps lasting for minutes
Bilateral leg cramps
Duration of cramps on feet
Circle of pain around the leg
Less severe cramps lasting less than 30s
Cramps in hamstrings quads and adductors
Nocturnal cramps lasting 10 to 20 minutes
Sudden onset of cramps
Cramps in hands
Cramps more in thighs
Impact: Evening/ Sleep
Created Harm/Danger
Lack of sleep affects work
Cramping in the pool
Waking up from sleep
Danger won't be able to get out of bath tub
Cramps in the evenings
Visiting ER due to severe cramps
Cramps start when getting home
from work
Cramps waking up at night due to
pain
Waking up due to cramps
Severe cramp caused a pulled knee ligament
Regular cramps causing disability
Did not miss work until recently when cramps
injured.
Cramp
Domains
Cramp
Severity
Cramp
Impact
Frequency
Duration
Cramp
Severity
Intensity
Location
Harm
Impairment
Day
Cramp Impact
Avoidance
Excessive
daytime
sleepiness
Night
Sleep
interference
Conclusions
 Neurogenic muscle cramps are a common and potentially
disabling condition in many disease states as well as normal
individuals
 Care must be taken to distinguish neurogenic muscle cramps
from other neurological and non-neurological phenomena
 A rational treatment approach should be used when treating
patients with muscle cramps
 In addition to exploring new pharmacological options for
treatment of muscle cramp, efforts should be made to ensure
cramp assessment are patient centered, comprehensive,
accurate and reliable across populations