Clinical features of muscle cramp in 14 dogs

Abstract Background Muscle cramps (MCs) are prolonged, involuntary, painful muscle contractions characterized by an acute onset and short duration, caused by peripheral nerve hyperactivity. Objectives To provide a detailed description of the clinical features and diagnostic findings in dogs affected by MCs. Animals Fourteen dogs. Methods Multicenter retrospective case series. Cases were recruited by a call to veterinary neurologists working in referral practices. Medical records and videotapes were searched for dogs showing MCs. The follow‐up was obtained by telephone communication with the owner and the referring veterinarian. Results Three patterns of presentation were identified depending on the number of affected limbs and presence/absence of migration of MCs to other limbs. In 9/14 (64%) of dogs, MCs were triggered by prompting the dogs to move. 8/14 (58%) dogs were overtly painful with 6/14 (42%) showing mild discomfort. The cause of MCs was hypocalcemia in 11/14 (79%) dogs: 9 dogs were affected by primary hypoparathyrodism, 1 dog by intestinal lymphoma and 1 dog by protein losing enteropathy. In 3/14 cases (21%) the cause was not identified, and all 3 dogs were German Shepherds. Conclusions and Clinical Importance Muscle cramps can manifest in 1 of 3 clinical patterns. Muscle cramps are elicited when dogs are encouraged to move and do not always appear as painful events, showing in some cases only discomfort. The main cause of MCs in this study was hypocalcemia consequent to primary hypoparathyroidism. In dogs having MCs of unknown etiology, idiopathic disease or paroxysmal dyskinesia could not be ruled out.


| INTRODUCTION
Muscle cramps (MCs) are prolonged, involuntary, painful muscle contractions, having acute onset and short duration, lasting from seconds to minutes. 1 In human medicine, cramps are classified in "silent" and "true" cramps. Silent cramps have a normal electromyography, often develop after intense exercise, and are associated with metabolic myopathies where there is a defect in glycolysis or glycogenolysis. 2 In dogs, a similar condition has not been described.
True MCs represent the expression of hyperexcitability of peripheral motor nerve. 3 In human medicine, on electromyography, the true MCs are characterized by repetitive motor unit action potentials generated by simultaneous contraction of a large number of motor units.
The number of motor units activated, and the frequency of their discharges increases gradually during the cramp (up to 150 Hz) and gradually stops according to the end of the event itself. 4 As for humans, in veterinary medicine, MCs are considered the clinical manifestation of nerve hyperexcitability. However, electromyographic documentation of these events is missing. 3 In humans, the diseases most commonly associated with MCs include disorders of the lower motor neuron (eg, amyotrophic lateral sclerosis, radiculopathies, neuropathies), metabolic disorders (eg, pregnancy, uremia, hypothyroidism, hypoadrenocorticism, hyperparathyroidism), conditions leading to the acute depletion of extracellular volume (eg, vomiting, diarrhea, diuretic therapies, hemodialysis), the use of certain drugs (eg, nifedipine, salbutamol, terbutaline, alcohol), and idiopathic forms (eg, exercise-related cramps and nocturnal cramps in elderly subjects). 5 Several disorders can result in episodic paroxysmal events that might mimic MCs, including seizures (epileptic and nonepileptic) or involuntary paroxysmal movement disorders (PMDs). 6 Due to the lack of reliable methods for the differentiation between epileptic and nonepileptic paroxysms, proper assessment of these episodes is sometimes challenging. 7 To date, in veterinary medicine, there is a lack of detailed description of MCs, limited to a few dogs affected by hypocalcemia and a single report of 2 poodles with hypoadrenocorticism. 8,9 The aim of this retrospective study was to provide a detailed description of the clinical features of MCs, assess the clinicopathological and diagnostic abnormalities, and describe the treatment and clinical course of the affected dogs. The data collected were inserted into an Excel file (Microsoft) and analyzed using a commercial statistical data analysis software (Prism 7.0a, GraphPad Software, Inc, San Diego, California).

| MATERIALS AND METHODS
The Shapiro-Wilk test was used to assess the normality of continuous data. Mean and SD calculations were reported for normally distributed data. Otherwise, the median and range were reported.
The t test was used to compare the serum ionized calcium concentration among the different patterns of clinical presentation and continuous variable between the group of hypocalcemic dogs and the group of dogs with MCs of unknown origin. According to the disease underlying MCs, dogs were divided into 2 groups: dogs with primary hypoparathyroidism vs other causes. The continuous variables (ionized calcium, total calcium, phosphorus, and magnesium) were compared using the Mann-Whitney test while the categorical variables (number of affected limbs and pain manifestations) were compared using the Fisher's exact test. The P-value <.05 was considered statistically significant.

| Animals
Fourteen dogs were included in the study (Table 1). Breeds represen-

| Investigation and diagnosis
After the completion of the diagnostic work-up, 11 dogs were hypocalcemic and for 3 dogs the etiological diagnosis remained unknown.
Among the hypocalcemic dogs, hypocalcemia was due to primary hypoparathyroidism in 9 cases. The other 2 dogs underwent an intestinal biopsy resulting affected by an intestinal lymphoma and a proteinlosing enteropathy (PLE), respectively. These 2 latter cases had a marked decrease of serum albumin and total protein concentrations.
In hypocalcemic dogs, the mean value of total calcium (measured in 12 dogs) and ionized calcium was 5.6 mg/dL (±1.7; normal refer- Abdominal US was performed in 7 cases; 2 dogs presented an abnormality of the intestinal wall; 5 dogs did not show any alteration.
Urinalysis was performed in 5 dogs, resulting normal in 1 case.
Two dogs had a decreased urinary specificity gravity, 1 dog had an increased urinary specificity gravity, 1 dog had a urinary infection due to Pseudomonas aeruginosa.

The 3 dogs with unknown etiological diagnosis were German
Shepherds ( Table 1). All of them were male and were significantly older at MCs onset than hypocalcemic dogs (P = .03). The duration of clinical signs before the diagnosis was not found statistically different between the 2 groups (P = .2).
All these 3 dogs showed PATTERN III (single limb pattern) MCs. Considering the group of dogs affected by primary hypoparathyroidism vs other causes, the total calcium (P = .04) and ionized calcium (P = .02) were significantly different between the 2 groups, being significantly lower in the group of the hypoparathyroid dogs. No significant differences were found for pain (P = .07), albumin, magnesium, and phosphorus (P = .9) between the 2 groups. Muscle cramps occurring as for the PATTERN III (single-limb pattern) could be even more difficult to be differentiated from a paroxysmal movement disorder (PMD). In veterinary medicine, paroxysmal dyskinesia has been used as a broad term to describe an abnormal, sudden, involuntary contraction of a group of skeletal muscles recurring episodically. 11 Similar to MCs, PMDs are not characterized by autonomic signs, consciousness is not impaired and abnormal postictal behavior is not observed. 12 Unlike MCs, PMDs are considered painless. 12 Nevertheless, even if not showing overt pain, dogs affected by PMDs could show signs of discomfort. 13 The objective demonstration of MCs in veterinary medicine remains difficult. Despite they present specific features on electromyography, this diagnostic test in dogs requires anesthesia and it is almost impossible to be performed during the attacks. 3 In our study, the etiological diagnosis of the MCs was not obtained in 3 dogs. All of them were male German Shepherds and had a PATTERN III (single-limb pattern) clinical presentation. They were suspected to suffer from MCs because the cramping attacks were almost identical to those of hypocalcemic dogs showing overt pain during the episode. These dogs did not undergo a complete diagnostic work-up including MRI or electrodiagnostic tests, therefore other causes, as PMDs, seizures, or MCs secondary to lower motor neuron diseases, could not be entirely excluded.

| Treatment and outcome
Despite not previously reported in veterinary medicine, it is not to reject the hypothesis that MCs, in this group of dogs, had an idiopathic origin. In people, when no causes are identified MCs are classified as idiopathic. 14 Idiopathic cramps notably include nocturnal leg cramps. 2,15 Although nocturnal muscle cramps occur at night, 20% of cases can have leg cramps primarily during the daytime. 16 Nocturnal leg cramps are more common in the elderly and typically involve the calf or foot muscles, frequently awaken the patient from sleep. The current hypothesis includes that they are secondary to the loss of motor neurons innervating the affected muscles and represent a similar phenomenon as that observed in patients with amyotrophic lateral sclerosis. 5 Various pharmacologic treatments have been studied for nocturnal leg cramps, including quinine. However, due to the severe adverse effect of quinine, stretching exercises are the sole indication to reduce MCs. 5 It is interesting to notice that all the dogs with MCs of unknown origin herein described, were significantly older than hypocalcemic dogs. The proposed theories include dehydration, altered plasma electrolyte concentrations, or α-motor neuron hyperexcitability. In this type of MCs, stretching relieves the signs without altering hydration or electrolyte status , demonstrating that restoring electrolyte and fluid balance is not a requisite for alleviating EAMC. Therefore, a neural mechanism, linked to α-motor neuron hyperexcitability, has been proposed. 17 The most common cause of MCs in this study was hypocalcemia.
According to the literature, dogs with chronic hypocalcemia display intermittent clinical signs, usually following periods of exercise or excitement. 18 The most common causes of hypocalcemia in dogs are hypoalbuminemia and renal failure. 19 Interestingly, in our case series, these conditions were uncommon, and 9 out of 11 hypocalcemic dogs were affected by primary hypoparathyroidism, a much rarer disease, possibly producing lower concentrations of ionized Calcium. 20 Hypomagnesemia can result in hypocalcemia. 19 Magnesium is an important cofactor for PTH secretion. In conditions of severe magnesium deficiency, parathyroid secretion is suppressed inducing hypocalcemia and hyperphosphatemia. Hypomagnesemia also induces a reversible resistance to the actions of PTH at the level of both bone and kidney. 21 In human medicine, hypomagnesemia is frequently undetected. Many patients with magnesium deficiency remain asymptomatic until serum magnesium concentration decrease to 0.5 mmoL/L or lower. 22 The earliest manifestations of magnesium deficiency are neuromuscular and neuropsychiatric signs. The most common clinical manifestations result from hyper-excitability, including positive Chvostek's and Trousseau's signs, tremor, fasciculation, and tetany. 23 In this case series, magnesium was measured in 7 dogs, and it was found decreased only in the hypocalcemic dog affected by PLE.
Unfortunately, our data are too limited to evaluate the possible role of magnesium in the onset of muscle cramps.
The major limitation of the present study consists of the small number of the dogs included in the study, which prevents to answer to many of the remaining open questions on MCs. For the same reason, statistical analysis was very limited and did not include breed and sex. Nevertheless, for the descriptive purposes of the study, it could be considered adequate, and robust statistical analysis not essential. It should be emphasized that it is extremely difficult to collect a relevant number of cases of MCs due to the rarity of this clinical manifestation.
An additional limitation can be found in the variability of the diagnostic and therapeutic protocols due to the retrospective multicentric nature of the study.

ACKNOWLEDGMENTS
No funding was received for this study. Presented as an abstract at the 32nd ESVN-ECVN Symposium in Wroclaw, Poland. Supporting Information Video S1 has been published in the national review Veterianaria as diagnostic corner-internal medicine 2020, 34 (1):31-33.

CONFLICT OF INTEREST DECLARATION
Authors declare no conflict of interest.

OFF-LABEL ANTIMICROBIAL DECLARATION
Authors declare no off-label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION
Authors declare no IACUC or other approval was needed.

HUMAN ETHICS APPROVAL DECLARATION
Authors declare human ethics approval was not needed for this study.