Case Communications IMAJ • VOL 14 • november 2012

Massive Indoor Cycling-Induced in a Patient with Hereditary Neuropathy with Liability to Pressure Palsy Marganit Benish PhD1, Inna Zeitlin MD2, Dana Deshet MD2 and Yitzhak Beigel MD1,2

1Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel 2Department of Medicine D, Wolfson Medical Center, Holon, Israel

profoundly decreased. Severe exercise-induced rhabdomyolysis, Key words: Patient Description and stiffness were observed when she hereditary neuropathy with liability A 21 year old female was hospitalized stretched both legs. She did not suffer to pressure palsy (HNPP), creatine kinase, indoor cycling, “spinning,” in December 2011 because of pain from any other medical condition and myoglobin and profound in her thighs had no history of recent exposure to IMAJ 2012; 14: 712-714 rendering her unable to walk, and tea- medications, vaccines, alcohol drinking, colored urine. The muscular symptoms or any signs and symptoms of a viral had begun 5 days prior to her admis- infection. Laboratory results showed a sion, starting immediately after she had CK level of 132,170 U/L (range < 10–145 participated, for the first time in her U/L) and increased transaminase levels habdomyolysis is a condition charac- life, in an indoor-cycling class (“spin- (alanine transaminase 280 U/L (< 3–31 R terized by extended myolysis, marked ning”) lasting 45 minutes. The color U/L), aspartate transaminase 1256 U/L elevation of serum creatine kinase and of her urine changed and prompted (< 3–32 U/L) [Table], serum sodium myoglobinuria. Weakness, , and her to immediately seek medical care. 140.5 mmol/L (136–148 mmol/L), tea-colored urine are the main clini- The patient has hereditary neuropathy potassium 3.78 mmol/L (3.6–5.3 cal manifestations. It may be caused by with liability to pressure palsy, an auto- mmol/L), calcium 8.6 mg/dl (8.6–10.2 prolonged exertion, trauma, hereditary somal dominant neuropathy, which mg/dl), phosphorus 3.6 mg/dl (2.7–4.5 enzyme defects, drugs, viral infections was diagnosed at the age of 12 follow- mg/dl), lactate dehydrogenase 6995 and alcohol abuse, and could lead to acute ing prolonged weakness in her fingers. U/L (240–480 U/L). Urine pH was 5.0, renal failure if not treated with hydration. However, she is generally healthy, dipstick measurement was positive for Indoor cycling, also known as “spinning,” recently completed her mandatory army blood, but no red blood cells were found has rarely been reported as a cause of service, and is physically active but had on microscopic examination, and the severe rhabdomyolysis, and rhabdomyoly- never attended an indoor cycling class test for myoglobin was positive. Blood sis in a patient with hereditary neuropathy before. Her mother and two siblings levels of urea, creatinine and other with liability to pressure palsy after indoor also carry this genetic abnormality and cycling has never been reported. reported that no other family member CK and transaminase levels We present an unusual case of a 21 with HNPP had ever been hospitalized AST ALT year old female with HNPP who pre- due to elevated CK levels or any other CK (U/L) (U/L) (U/L) sented with a creatine kinase level of rhabdomyolysis-related symptoms. DAY 1 132,170.0 NA NA (admission) 132,170 U/L after participating in an On admission, physical examina- indoor cycling workout for the first time tion revealed an alert and well-oriented DAY 2 126,740.0 1636 382 in her life. We describe the treatment for young woman who moved with diffi- DAY 3 91,680.0 NA NA this patient, the risks of rhabdomyolysis, culty and needed assistance when walk- DAY 4 28,938.0 892 NA and the potential vulnerability of people ing. Her pulse was 104 beats/minute. DAY 5 7890.0 NA NA with neuropathies to rhabdomyolysis. Bilateral tenderness was observed on DAY 6 3781.0 225 238 palpation of both quadriceps. Muscle (Discharge)

strength in the lower extremities was CK = creatine kinase, AST= aspartate HNPP = hereditary neuropathy with liability to transaminase, ALT= alanine transaminase, NA = data not available pressure palsy CK = creatine kinase

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routine tests were normal. Severe rhab- level ≥ 5 times the upper limit of normal shown in several models to be nephro- domyolysis was diagnosed. In order to (approximately 750 U/L). A minimal toxic by various underlying mechanisms avoid hypernatremia, intravenous fluid laboratory workup in rhabdomyolysis [3]. These mechanisms include: a) contri- resuscitation with NaCl 0.45% was initi- includes serum levels of CK, calcium, bution to renal vasoconstriction (mainly ated, together with sodium bicarbonate electrolyte renal functions, in conjunc- in hypovolemic patients), b) interaction (0.5 g/L) for alkalinization of the urine. tion with detection of myoglobin in with Tamm-Horsfall proteins and for- Fluid resuscitation was then contin- urine and an electrocardiogram. Some mation of intraluminal casts, and c) ued with NaCl 0.9%. During the first cases of rhabdomyolysis include the direct toxicity via lipid peroxidation and 24 hours of treatment the urine color development of , tubular injury. These mechanisms were returned to normal. for which magnetic resonance imaging also shown to be potentiated by acidic The differential diagnosis for has recently emerged as a diagnostic pH of tubular fluid [3]. includes primary modality [1]. The mainstay of therapy is directed muscle diseases (congenital dystro- Causes for rhabdomyolysis include toward appropriate urine output, phies, inflammatory, or metabolic) or traumatic muscle injury, increased vol- achieved by aggressive intravascular secondary muscle diseases (following untary or involuntary muscle activity, volume expansion with normal saline in infections, connective tissue diseases, exogenous toxins, alcohol and illicit order to correct hypovolemia, promote endocrine dysfunction, paraneoplas- drugs, drugs (such as statins), viral infec- vigorous diuresis and dilute the released tic, or drug-induced), neuromuscular tions, hereditary , and hered- toxic products. Additionally, alkaliniza- junction disorders (e.g., myasthenia itary inflammatory muscle diseases. tion of the urine to a pH < 6.0 was shown gravis or Lambert-Eaton), or upper or Exercise-induced rhabdomyolysis is to prevent the development of acute lower motor neuron problems (such as typically seen in high endurance athletes renal failure, but the use of bicarbonate Guillain-Barré syndrome, or toxins, involved in marathons, triathlons and and mannitol is still under debate [1]. metabolic disorders, nutrition, infec- super marathons, but was also occasion- HNPP (“tomaculous neuropathy”) is tion, immune related and hereditary). ally reported in low and high intensity an autosomal dominant disease clinically Our patient described an etiology and workouts. In the past, it was suggested characterized by a recurrent episodic medical history that seemed appropriate that muscle fiber-type proportions can neuropathy localized to areas frequently for rhabdomyolysis with extraordinarily be an underlying contributing cause of affected by compression or trauma [4]. high levels of serum CK. exercise-induced rhabdomyolysis. When The neuropathy is followed by a spon- After 4 days, IV hydration was re- reviewing the literature, we found that taneous slow recovery. In most patients, placed with oral hydration of 3 L/day. most CK levels in rhabdomyolysis were symptoms first appear in the second The patient was released on the sixth below 100,000 U/L. Indoor cycling decade. The commonly affected nerves day of hospitalization. Weakness of the (“spinning”), as in our patient, has are those located in trauma-afflicted lower extremities was still profound, but been infrequently reported as a cause of sites and include the axillary, median, she was now able to walk. exercise-induced rhabdomyolysis, and radial, ulnar and peroneal nerves, and/ CK elevation above 100,000 U/L was or the brachial plexus. Genetically, most recently described only in male athletes patients with HNPP exhibit a large 1.5 Comment after vigorous training [2]. Mb deletion in chromosome 17p11.2-12 Rhabdomyolysis is a condition of muscle The standard of care for rhabdomyol- that results in reduced expression of the necrosis and release of intracellular ysis is directed at the prevention of renal peripheral myelin protein 22 (PMP22) muscle constituents into the circulation, failure, hyperkalemia, metabolic acido- gene [4], making nerves more susceptible associated with symptoms ranging from sis, and hypovolemia [1]. Myoglobin is a to minor trauma or compression. an asymptomatic elevation of CK levels compound released from damaged mus- DNA analysis by FISH (fluorescence to severe muscular pain, weakness and cle cells to the circulation, where it binds in situ hybridization) is available for even paralysis accompanied by electro- to haptoglobin. During rhabdomyolysis, confirmation of the HNPP diagnosis. A lyte abnormalities, myoglobinuria and excessive levels of myoglobin remain unique histological feature seen in sural renal failure [1]. The clinical diagnosis unbound and are therefore rapidly nerve biopsies is a focal sausage-like is based on complaints of muscle pain excreted in the urine, often resulting in thickening of myelin sheaths (tomacula) or weakness in the presence of elevated the production of red/brown urine. As in [4]. Electrophysiological studies show a serum CK. Although there are no clear our patient, myoglobinuria presented as distinctive sensorimotor neuropathy definitions regarding CK levels in rhab- tea-colored urine with a dipstick positive pattern that can help to establish the domyolysis, clinical practice guidelines for blood, while no erythrocytes were diagnosis. This pattern is character- for rhabdomyolysis define a serum CK seen on microscopy. Myoglobin was ized by a diffuse slowed sensory nerve

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conduction velocity and a prolongation tion. Interestingly, duplication or dele- with HNPP consult a sports medicine of distal motor latencies (the interval tion of the same chromosomal region, specialist and routinely measure blood between the stimulus and the onset of which contains the gene for PMP22, CK following increases in exercise the compound muscle action potential), leads to the development of CMT type intensity in order to detect abnormal while the motor conduction velocity is 1A or HNPP, respectively [4]. Although signs that could precede rhabdomy- barely reduced. This indicates a dis- CMT and HNPP are related to a defect olysis. proportionate distal-conduction slow- in the same protein, both disorders are ing typical to this disorder [4]. Nerve different and there is no evidence for Corresponding author: Dr. M. Benish conduction velocity abnormalities are increased risk for rhabdomyolysis in Sackler Faculty of Medicine, Tel Aviv University, not restricted to the nerves, which are either pathology. However, the exact Ramat Aviv 69978, Israel affected by palsy, but are found in a gen- role of PMP22 is still unknown, and it Fax: (972-3) 640-9520 email: [email protected] eralized pattern and even in muscles of may be hypothesized that alterations asymptomatic gene carriers [4]. in its expression could predispose to References Whether our patient’s HNPP played higher vulnerability toward intra- and 1. Bagley WH, Yang H, Shah KH. Rhabdomyolysis. a role in her severe rhabdomyolysis extracellular electrolyte perturbations Intern Emerg Med 2007; 2 (3): 210-18. may only be speculated. In 2001, Brncic and calcium load in both CMT-1A and 2. Cleary MA, Sadowski KA, Lee SY, Miller GL, et al. [5] described a case of Salmonella HNPP patients, resulting in rhabdo- Nichols AW. Exertional rhabdomyolysis in an infection-related rhabdomyolysis in myolysis and elevated CK levels. The adolescent athlete during preseason conditioning: a perfect storm. J Strength Cond Res 2011; 25 (12): a patient with Charcot-Marie-Tooth association between the two patholo- 3506-13. disease [5]. CK levels were 64,000 U/L. gies described in this patient might 3. Holt S, Moore K. Pathogenesis of renal failure CMT disease results in denervation seem weak; nevertheless, we believe in rhabdomyolysis: the role of myoglobin. Exp and trophic and metabolic changes in that such a link does exist and should Nephrol 2000; 8 (2): 72-6. nerves and muscles. Brncic and team be further examined in animal models 4. Chance PF. Inherited focal, episodic neuropathies: hereditary neuropathy with liability to pressure [5] suggested that CMT might be a pre- and clinical assessments. palsies and hereditary neuralgic amyotrophy. disposing factor to rhabdomyolysis and Patients with HNPP are advised to Neuromolecular Med 2006; 8 (1-2): 159-74. therefore might be of major significance avoid using excessive force, repetitive 5. Brncic N, Viskovic I, Sasso A, Kraus I, Zamolo in the development of this complica- movements, and extreme or static joint G. Salmonella infection-associated acute rhab- domyolysis. Some pathogenic considerations. Arch CMT = Charcot-Marie-Tooth positions. We also suggest that patients Med Res 2002; 33 (3): 313-15.

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