CASE STUDIES IN TOXICOLOGY Series Editor: Lewis S. Nelson, MD Diffuse Muscle Weakness: The Toxicologist’s Approach Colleen Rivers, MD, and Lewis S. Nelson, MD The differential diagnosis is daunting in this case of an elderly woman with new-onset inability to walk. However, results of her lab work and other testing provide important clues that ultimately point to her medication regimen. Case What is a practical toxicologic differential An 81-year-old woman presents to the ED with a 5-day diagnosis for diffuse muscle weakness? history of generalized weakness and dyspnea. She de- There are numerous etiologies for muscle weakness, in- nies sensory symptoms, diplopia, dysarthria, and dys- cluding infectious, metabolic, autoimmune, endocrine, phagia. Her medical history includes hypertension, and toxicologic causes. One approach to this daunting hyperlipidemia, and atrial fibrillation. Her surgical differential diagnosis considers whether the pathology history is notable for a remote thymectomy. She is cur- originates within the peripheral motor neuron, at the rently taking warfarin, digoxin, and simvastatin. neuromuscular junction, or within the muscle itself. On physical examination, her vital signs are within This framework subsequently allows the history, physi- normal limits. She is awake, alert, and cooperative. cal exam findings, and clinical progression to further Her cardiac, pulmonary, and abdominal exams are all narrow the list of likely causes. unremarkable. On neurologic examination, her cra- The classic clinical findings of neuronal dysfunction nial nerves II through XII are intact. She has bilateral leading to paralysis are exemplified in a demyelinat- upper extremity weakness (4/5) that is slightly worse ing syndrome such as Guillain-Barré syndrome (GBS). proximally compared to distally. She has bilateral lower This condition typically presents as an ascending motor extremity weakness (2/5) that is also slightly more pro- weakness in the 2 to 4 weeks following a viral illness or nounced in the proximal muscle groups. Her neck Campylobacter jejuni infection. Symptoms often begin flexion is weak (3/5), deep tendon reflexes are absent with paresthesias of the distal extremities, followed by throughout, and she is unable to walk. Perception of weakness that may progress to involve the trunk, upper light touch is intact throughout. Her proximal muscles extremities, cranial nerves, or diaphragm over a period are slightly tender to palpation, and their consistency of days to weeks. Deep tendon reflexes tend to be absent is normal. early in the disease course, and objective sensory deficits are rare.1 Muscle pain or tenderness does not occur. Dr. Rivers is a senior fellow in medical toxicology in the Toxicologic mimics such as tick paralysis and bot- department of emergency medicine at the New York University School of Medicine in New York City and the ulism, resulting from the inhibition of acetylcholine New York City Poison Control Center. Dr. Nelson, editor release at the neuromuscular junction, similarly pres- of “Case Studies in Toxicology,” is an associate professor ent with diplopia, dysphagia, and other manifestations in the department of emergency medicine and director of the medical toxicology fellowship program at the New York of cranial nerve dysfunction. This is followed by de- University School of Medicine and the New York City Poison scending paralysis with consequential involvement Control Center. He is also a member of the EMERGENCY 2 MEDICINE editorial board. of the respiratory musculature. GBS may present as a descending paralytic syndrome as well, and this is 22 EMERGENCY MEDICINE | DECEMBER 2011 www.emedmag.com Table. Nontoxicologic Causes of Diffuse Muscle Weakness Etiology Mechanism Clinical Presentation Lambert-Eaton Presynaptic voltage-gated • Starts with proximal leg weakness syndrome4 calcium channels blocked by • Slowly progressive autoantibodies • Improves with exertion • Possible diaphragm involvement Myasthenia gravis4 Postsynaptic nicotinic • Starts with diplopia, cranial neuropathies ACh receptors blocked by • Worsens with repeated effort autoantibodies • Possible diaphragm involvement Primary periodic Alterations in L-type calcium • Attacks of flaccid paralysis sparing facial muscles paralyses channel or skeletal muscle • Rare diaphragm involvement (hyperkalemic sodium channel subunits • Common after exercise or large carbohydrate or hypokalemic)5 meal Myopathies Infection (eg, influenza) • Muscle pain Autoimmune (eg, lupus) • Proximal limb weakness Endocrine (eg, hypothyroidism) • Elevated CPK level ACh = acetylcholine; CPK = creatine phosphokinase. Data from Wirtz et al4 and Venance et al.5 known as the Miller Fisher variant. (normal <40 U/L); blood urea nitrogen, 68 mg/dL; A variety of toxic-metabolic derangements, such as and creatinine, 2.3 mg/dL. A lumbar puncture is per- hypermagnesemia3 or hypokalemia, can affect trans- formed, with cerebrospinal fluid (CSF) showing no red mission at the neuromuscular junction and result in or white blood cells and normal protein and glucose weakness or flaccid paralysis. Both of these electrolyte measurements. The patient is admitted to the hospital abnormalities alter neuronal excitability—hypokale- and undergoes nerve conduction studies (NCS) with mia, by changing the electrochemical potential of excit- unremarkable results and electromyography (EMG) able cells, thus blocking repolarization; and hypermag- with abnormal findings that are consistent with the nesemia, by blocking presynaptic calcium ion entry. In diagnosis of myopathy. patients with severe electrolyte abnormalities, altera- tions in cardiac conduction can also occur. However, How should the potential etiologies of muscle pain is not expected. diffuse muscle weakness be approached? Finally, myopathies are a group of disease processes Clinical features of the history and physical examina- that affect the muscle fibers themselves, resulting in tion assist in the differential diagnosis. For example, in symmetrical weakness that tends to involve the more this patient, the weakness is localized to her limbs and proximal muscle groups. Patients may complain of trunk with no cranial nerve abnormalities—a finding muscle pain and have muscle tenderness on palpation. that lowers the likelihood of either botulism or myas- Although congenital disorders are a common cause in thenia gravis. infancy (Duchenne muscular dystrophy), acquired my- Also, initial laboratory studies from the ED, includ- opathies in adults are commonly related to use of medi- ing electrolyte, CSF, and CPK measurements, can help cations such as corticosteroids, zidovudine, colchicine, differentiate among these causes. In this case, normal and statins. The Table summarizes nontoxicologic eti- serum potassium and magnesium concentrations es- ologies of diffuse muscle weakness. sentially rule out hypermagnesemia or hypokalemia as causes of weakness. Lumbar puncture was performed Case Continuation to identify GBS by looking for “cytoalbumin dissocia- The patient’s initial laboratory values are notable for the tion.” This classic CSF finding of an elevated protein following: creatine phosphokinase (CPK), 3,513 U/L level and a normal white blood cell count suggests GBS www.emedmag.com DECEMBER 2011 | EMERGENCY MEDICINE 23 CASE STUDIES IN TOXICOLOGY but is not always present in the first few days of the as well as an intracellular antioxidant.6 As a result, CoQ disease process. Still, a normal CSF protein level and supplementation has been studied as a treatment for cell count, which are seen in this case, make GBS an statin-associated myalgias (with sporadic success).7,8 unlikely etiology. Additionally, this patient’s elevated Statins undergo glucuronidation, and coadministra- serum CPK level of 3,513 U/L, reflecting muscle break- tion of other drugs that undergo glucuronidation, such down and release of myocyte contents into the systemic as gemfibrozil, may increase blood statin concentra- circulation, suggests myopathy as an etiology. Eleva- tions.9 Additionally, most statins are metabolized by the tions in serum CPK sometimes occur in conjunction CYP3A4 enzyme system. Concurrent administration with a reddish discoloration of urine and a urine dip- of drugs that are also metabolized by this enzyme, such stick result that is positive for blood in the setting of a as macrolide antibiotics, nondihydropyridine calcium urinalysis that is negative for red blood cells—pointing channel blockers, and protease inhibitors, may increase to the presence of urinary myoglobin. blood statin concentrations.9 Lastly, a number of studies can be performed during While decreased levels of CoQ and elevated statin hospitalization to further narrow the differential diag- concentrations due to drug interactions are biologi- nosis. For example, this patient underwent NCS, which cally plausible mechanisms for statin toxicity, the ex- may be helpful to diagnose diseases of neuronal trans- act mechanism has not yet been fully elucidated. Some mission, such as GBS. In this test, a peripheral nerve is suggest that multiple minor metabolic abnormalities electrically stimulated, and the time it takes the impulse place patients at risk for muscle complications during to travel to the motor end plate is measured. As was the statin therapy.10 In such patients, any lipid-lowering case with this patient, NCS may be ordered with EMG. drug that results in decreased delivery of fat substrate EMG evaluates the electrical activity of muscle cells by to muscles might