Asymmetric flaccid paralysis A neuromuscular presentation of West Nile virus infection.код для вставкиСкачать
ORIGINAL ARTICLES Asymmetric Flaccid Paralysis: A Neuromuscular Presentation of West Nile Virus Infection Jun Li, MD, PhD,1 Jeffrey A. Loeb, MD,1,2 Michael E. Shy, MD,1,2 Aashit K. Shah, MD,1 Alex C. Tselis, MD,1 William J. Kupski, MD,3 and Richard A. Lewis, MD1 The neuromuscular aspects of West Nile virus (WNV) infection have not been characterized in detail. We have studied a group of six patients with proven WNV infection. All cases presented with acute, severe, asymmetric, or monolimb weakness, with minimal or no sensory disturbance after a mild flu-like prodrome. Four cases also had facial weakness. Three of our cases had no encephalitic signs or symptoms despite cerebrospinal fluid pleocytosis. Electrophysiological studies showed severe denervation in paralyzed limb muscles, suggesting either motor neuron or multiple ventral nerve root damage. This localization is supported further by the finding of abnormal signal intensity confined to the anterior horns on a lumbar spine magnetic resonance imaging. Muscle biopsies from three patients showed scattered necrotic fibers, implicating mild direct or indirect muscle damage from the WNV infection. In summary, we describe a group of patients with acute segmental flaccid paralysis with minimal or no encephalitic or sensory signs. We have localized the abnormality to either the spinal motor neurons or their ventral nerve roots. It will be important for physicians to consider WNV infection in patients with acute asymmetric paralysis with or without encephalitic symptoms. Ann Neurol 2003;53:703–710 West Nile virus (WNV) is a RNA virus that belongs to the flavivirus family taxonomically.1 The dramatic outbreak of WNV infection in New York City in 1999 heralded the virus reaching North America.2 Since then, WNV has rapidly spread across the United States. There were only 142 cases with 18 deaths between 1999 and 2001. However, during the summer of 2002, the incidence of WNV infection drastically increased to a total of 3,052 cases with 153 deaths to date.3 Ten percent of patients with WNV infection from Israel and New York City presented with acute, bilateral flaccid paralysis.2,4 The findings from their electromyography and nerve conduction studies were not described in detail but were interpreted as axonal motor neuropathy, imitating Guillain–Barré syndrome.2 There also have been a few case reports describing patients with WNV infection and a “poliolike” syndrome.5–7 During this past summer (2002), Michigan had a significant number of cases of WNV infection. In this report, we describe a group of WNV-infected patients presenting with a peculiar acute segmental flaccid pa- ralysis. We provide detailed electrophysiological and neuroimaging evidence that this disorder is localized to the anterior horn motor neurons and/or ventral roots of the spinal cord. From the 1Department of Neurology, 2Center for Molecular Medicine and Genetics, and 3Department of Pathology, Wayne State University School of Medicine, Detroit, MI. Address correspondence to Dr Li, Department of Neurology, Wayne State University, 4201 St. Antoine, UHC-8D, Detroit, MI 48201. E-mail: email@example.com Patients and Methods Six patients, four men and two women, were examined, ranging in age from 27 to 63 years old. Workup included magnetic resonance imaging (MRI) of the brain and spine, lumbar puncture, electrophysiology, and muscle /nerve biopsy. Four of these patients had positive IgM antibodies to WNV by enzyme-linked immunosorbent assay (ELISA) test of their cerebrospinal fluid (CSF), performed in the Department of Health of the State of Michigan. The remaining two cases had positive IgM antibodies in the serum with positive neutralizing antibody test, which is also confirmatory. Results Case Reports Laboratory and neuroimaging results for all cases are listed in Table 1. Received Nov 21, 2002, and in revised form Feb 19, 2003. Accepted for publication Mar 7, 2003. © 2003 Wiley-Liss, Inc. 703 Table 1. Laboratory and Neuroimaging Results Patient No. Test 1 2 Brain MRI Normal Normal Spine MRI Normal Normal CSF (day) Cell and differentiation Day 20 RBC 22, Nuc 61 L 84% 171 77 220 ⫹ In CSF Day 1 RBC 10, Nuc 32 L 85% 96 84 17,808 ⫹ In CSF protein Glucose CK WNV IgM ab a 3 4 Not done; head CT: a 1cm mass in pituitary Not done Not done; head CT: normal Not done Day 25 RBC 1140, Nuc15 L 90% Day 2 RBC 14, Nuc 425 L 24% 83 72 28 ⫹ In serum 145 80 — ⫹ In CSF 5 6 Normal Normal Stenosis at C3-7, intact cord; T/L/S spine MRI: normal Day 9 RBC 33, Nuc 4 L 81% Abnormal signal intensity at anterior horn of C/L cord Day 7 BC 10, Nuc 150 L 24% 193 67 — ⫹ In serum 52 66 141 ⫹ In CSF and serum Days after onset of symptoms. MRI ⫽ magnetic resonance imaging; C/L ⫽ cervical/lumbar; CT ⫽ computed tomography; CSF ⫽ cerebrospinal fluid; L ⫽ lymphocytes; RBC ⫽ red blood cell; T/L/S ⫽ thoracic/lumbar/sacral; WNV ⫽ West Nile virus. PATIENT 1. A 36-year-old woman was healthy until 1 week before presentation when she developed mild “flu-like” symptoms, including headache, malaise, and gastrointestinal upset. One day before admission, she noted lower back pain. On the morning that she came to the hospital, she awoke to find her left leg paralyzed. At no time did she have confusion, neck stiffness, or other meningoencephalitic symptoms or signs. She denied bowel and bladder dysfunction or muscle pain. Examination showed a temperature of 38.2°C and a flaccid left leg without movement except for minimal ankle dorsal and plantar flexion. There was minimally reduced sensation to pinprick in the leg and absent left knee and ankle deep tendon reflexes. All other reflexes were well preserved, and the rest of her examination was normal. She received a course of intravenous immunoglobulin treatment (1gm/kg/day for 2 days) with no significant improvement. After 5 months, there had been no improvement of her motor deficit. PATIENT 2. Six days before admission, this 45-year-old man fell on the steps of his front porch and found that his left leg was weak. He struggled to stand up and was able to walk only a few blocks. The weakness in this leg progressed over the next hour to the point that he could no longer walk or even support himself. He had significant diarrhea 1 day before admission. He had one incident of bowel incontinence, but it was unclear whether the incontinence was from diarrhea or secondary to sphincter dysfunction. He denied muscle pain. There was no fever, headache, or neck stiffness. The day after admission, he was noted to be confused. 704 Annals of Neurology Vol 53 No 6 June 2003 His examination on day 2 showed a temperature of 36.6°C, disorientation to time and place, and mild nystagmus on lateral gaze to the right and bilateral facial weakness including frontalis muscles. Muscle examination showed 2/5 strength in the left leg and 4/5 strength in the right leg. Sensory examination was normal for vibration and equivocal to pinprick in the left leg. Deep tendon reflexes were absent in the left knee and ankle, but normal in other limbs. His mental status returned to normal over 4 days, but his weakness persisted. A 27-year-old man with a history of alcohol abuse presented with diarrhea, vomiting, and generalized fatigue approximately 2 weeks before admission. Six days before admission, he fell while climbing stairs. The next morning, he awoke with right arm paralysis. Within 2 to 3 days, the left arm also became mildly weak. He denied sensory disturbance, muscle pain, and bowel and bladder dysfunction. There was no alteration of mental status. He did not have headache, fever, or neck stiffness. His examination showed a normal temperature and mental status. There was neck flexor and bilateral facial weakness including frontalis muscles, 0/5 strength in the right arm and 4/5 in the left arm. There was minimal weakness of both legs. Sensory examination was normal. Deep tendon reflexes were normal in the left arm but were reduced in all other limbs. He received a course of intravenous immunoglobulin (1gm/kg/day for 2 days), which did not alter his motor deficit. A telephone interview 2 months later suggested that his arm weakness persisted. PATIENT 3. PATIENT 4. A 48-year-old man with a previous medical history of diabetes and non-Hodgkin’s lymphoma (cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone chemotherapy completed 2 years earlier) developed diarrhea, vomiting, and abdominal cramps and generalized fatigue 4 days before admission. On the day of admission, he acutely became unable to walk and developed a flaccid left arm. He denied any sensory disturbance, muscle pain, and bowel and bladder incontinence. He became disorientated soon after admission but improved the following week. He denied fever, headache, or neck stiffness before admission. His examination showed a low-grade fever (38.3°C) and disorientation to time and place. There was bilateral facial weakness including frontalis muscles, 0/5 strength in the left arm, 4/5 in the right arm, and 3/5 in both legs. Sensory examination was unremarkable. Deep tendon reflexes were normal in the right arm but otherwise reduced throughout. By telephone interview 1 month later, the patient reported that his leg strength improved enabling him to walk with a walker; however, his arm weakness remained the same. PATIENT 5. A 63-year-old healthy man awoke 6 days before admission with pain in the middle of his back and found that his left leg was weak and that he was unable to walk. There were no sensory symptoms, muscle pain, or bowel and bladder dysfunction. He denied fever, malaise, gastrointestinal discomfort, headache, neck stiffness, and confusion. His examination showed normal temperature, mental status, and cranial nerve function. His left leg was flaccid except for minimal flexion of the knee and ankle joints. The strength of the right leg was mildly reduced (4/5), but strength in upper limbs was normal. Pinprick, light touch, and vibration modalities were symmetrically reduced in the distal legs and feet, with noticeable hammertoes and high-arch feet. Deep tendon reflexes were normal in all joints but were absent in both ankles. The tone of the anal sphincter was normal. By telephone interview 5 months later, the patient reported that his leg weakness remained the same. A 51-year-old healthy woman developed “flu-like” symptoms 1 week before hospitalization. Two days after admission, her right leg became paralyzed. Her left arm also became weak. The weakness quickly spread to the left leg and right arm but was less severe. She was bed-bound. She had diffuse back muscle aching, but no other sensory disturbance. The patient denied bowel and bladder incontinence. She had a fever of 38.8° C and a stiff neck upon admission. The patient was not evaluated by us until 5 months after the onset of her symptoms. At this time, she had PATIENT 6. normal cranial nerve function, severe weakness (1–2/5) in the right leg, and mild to moderate weakness (3– 4/5) in her other limbs. Sensory examination was normal. Deep tendon reflexes were brisk in all joints with down-going toes. Her strength has improved over 5 months from being bed-bound to ambulating with a wheeled walker. Highlights of Laboratory Findings Four patients had positive IgM antibodies to WNV detected by ELISA on the CSF. These patients were considered confirmed cases of WNV. Patients 4 and 5 had positive IgM antibodies in the serum with positive neutralizing antibody test, which was also confirmatory.8 No ELISA test was conducted on the CSF of Patients 4 and 5. Patient 2 had a markedly elevated creatine kinase level. Because the patient fell 6 days before presentation, the creatine kinase level could be related to muscle injury, but the creatine kinase level elevation persisted for more than 12 days, making a traumatic cause less likely. CSF examination showed protein elevation and pleocytosis with lymphocytic predominance in four patients (see Table 1). Patient 4 had 76% neutrophils initially but converted to 93% lymphocytes in the second CSF examination collected 4 days later. MRI studies in Patients 1 and 2 did not show abnormalities in the brain or spinal cord. Cervical MRI in Patient 5 showed degenerative changes causing stenosis at C3 to C7, but the cord was normal. The spine MRI of Patient 6, performed 3 days after the onset of weakness, was remarkable for showing focal abnormal signal intensity within the anterior horns on T2weighted images (see Fig 1). The level of abnormal MRI findings corresponded to the weakness. No abnormal signals were found in roots, nor were roots enhanced after injection of contrast. Routine blood counts were normal in three patients, but one had increased leukocytes (Patient 3) and two had reduced platelets (Patients 3 and 4). Sedimentation rates were only performed in Patients 1 and 3 and were markedly elevated. Electrophysiology Motor nerve conduction studies showed severely reduced amplitudes of compound muscle action potentials in symptomatic limbs (Table 2). Nerve conduction velocities (CVs) in these limbs were relatively preserved. All patients whose CVs were mildly reduced also had very low amplitudes of their compound muscle action potential, making it probable that the decreased CVs were caused by severe axonal loss. Sensory nerve conduction studies were normal except for Patients 4 and 5 who had a history of diabetes and hammertoes/high-arch feet (possibly a pre-existing neuropathy), respectively. Patient 1 had a conspicuous Li et al: Segmental Flaccid Paralysis 705 weak limbs and the corresponding paraspinal muscles (Table 3). Taken together, the pattern of striking denervation in muscles of the paralyzed limbs and corresponding paraspinal muscles with relative sparing of sensation localizes the lesions to the anterior horn motor neurons and/or their ventral nerve roots. The localization was further corroborated by the aforementioned MRI abnormalities at the anterior horns. Thus, anterior horn cell damage is a plausible explanation for the weakness in most, if not all, patients. Interestingly, needle electromyogram showed myopathic changes in two to three muscles of Patients 3 and 6, whereas other clinically affected muscles had neurogenic alterations. This finding may be consistent with the findings of the three muscle biopsies (Fig 2) with abnormalities described below. Muscle and Nerve Histology We performed nerve and muscle biopsies on four patients (see Fig 2). Muscle biopsies of Patients 1 and 2 showed scattered necrotic muscle fibers, which were invaded by macrophages. In Patient 5, inflammatory cells were found around small vessels (Fig 3). Because of the small size of the vessels, we could not be certain if vessel walls were necrotized. The muscle biopsy of Patient 3 was normal. The sural nerve biopsy from Patient 1 showed only occasional degenerated axons with scattered ovoids. Nerve biopsy of Patient 2 was normal. In an attempt to provide evidence of direct invasion of muscle by WNV, we performed immunohistochemistry on the biopsied muscle from Patient 2 with polyclonal antibodies against Japanese encephalitis serocomplex flavivirus, an antibody that also labels other flaviviruses including WNV. The muscle did not show reactivity with these antibodies. Fig 1. Abnormal magnetic resonance imaging (MRI) signal intensity at the anterior horns of spinal cord. (A) A sagittal T2-weighted MRI of the lumbar spinal cord. Abnormal signal intensity (arrows) is conspicuous within the cord. (B) A transverse view of the cord at the midlumbar level. Abnormal signal intensity (arrows) is confined to the anterior horns. asymmetry of sural and superficial peroneal nerve responses in the symptomatic left leg. Needle electromyogram showed severe denervation in muscles of 706 Annals of Neurology Vol 53 No 6 June 2003 Discussion We have identified several WNV cases presenting with predominantly motor deficits at the level of the anterior horn motor neurons and/or their ventral roots. This acute segmental flaccid paralysis has several unique features compared with other neurological presentations related to WNV infection.2,5–7 These patients have a primarily neuromuscular disorder with minimal or no viral prodrome. The weakness was markedly asymmetric or involved only a single limb and progressed over minutes or hours to paralysis. There was conspicuous denervation by needle electromyogram and minimal or no sensory involvement by nerve conduction study. Three patients (1, 3, and 5) had no clinical meningoencephalitic signs or symptoms, although they did have pleocytosis in their CSF. Three patients had no fever upon presentation. Unlike other reports to date,2,5,6 most of our patients were not elderly or immunosuppressed. The pathogenesis of acute segmental flaccid paralysis Table 2. Eletrophysiology 1a (day 5) Nerves Norms R L Lower extremity nerve conduction studies Peroneal DML ⬍5.5msec 5.4 6.0 CV ⬎41m/sec 47 49 Amp ⬎3mv 4.3 0.5 F ⬍56msec 55 NR Tibial DML ⬍6.0msec 5.0 7.0 CV ⬎41m/sec 46 45 Amp ⬎4mv 5.0 1.0 F ⬍58msec 57 NR Sural Lat ⬍4.5msec 3.8 4.2 CV ⬎35m/sec 47 45 Amp ⬎6V 17 11 Sup per Lat ⬍4msec 3.6 4.2 CV ⬎35m/sec 54 41 Amp ⬎5V 21 9 Upper extremity nerve conduction studies Median motor DML ⬍4.5msec 3.6 — CV ⬎50m/sec 57 Amp ⬎4mv 9.3 F ⬍32msec 30 Ulnar motor DML ⬍3.5msec 3.0 — CV ⬎50m/sec 57 Amp ⬎6mv 10 F ⬍32msec 28 Medi sen Lat ⬍3.5msec 3.2 — CV ⬎45m/sec 56 Amp ⬎20V 35 Ulnar sen Lat ⬍3.5msec 3.5 — CV ⬎45m/sec 50 Amp ⬎10V 35 2 (day 10) 3 (day 7) R L R 5.4 38 2.6 NR NR — 4b (day 11) L R 3.9 43 3.2 50 — — — 5.5 46 11 53 — 3.9 44 9.3 3.8 47 12 4.6 37 21 — — — 5b (day 6) 6 (5 mo) L R L R L 8.0 33 0.1 — NR NR NR NR 7.0 29 0.3 NR — 5.9 36 2.0 65 6.5 37 6.5 66 6.4 39 3.0 54 — — NR 3.5 40 8.5 NR 4.1 35 7 5.1 36 10 — — — NR NR — — — 6.0 44 2.0 39 4.6 47 4.0 32 5.0 45 2.0 NR 3.9 50 4.5 34 5.0 52 5.4 — 4.0 52 8.0 31 4.0 51 6.0 29 — — 5.2 44 1.0 36 3.3 51 3.0 31 3.7 45 4.0 NR 3.3 50 4.6 36 3.1 57 7.6 31 2.8 56 8.0 28 — — 4.3 42 41 3.4 56 39 4.0 48 11 4.1 44 9.2 2.9 48 23 3.5 50 26 3.8 47 29 — — 4.4 41 52 3.4 50 50 3.9 45 7.0 3.8 47 11 — 3.3 54 17 3.5 54 27 6.5 38 0.6 NR a Days after onset of weakness. Patient 4 received prior cyclophosphamide, hydroxydaunomycin, vincristine, prednisone chemotherapy and has a history of diabetes, which may contribute to the conduction abnormalities. Patient had evidence of pes cavus suggesting a possible pre-existing neuropathy. b DML ⫽ distal motor latency; CV ⫽ conduction velocity; L ⫽ left; R ⫽ right. is unknown currently but probably involves the anterior horn motor neurons or their ventral nerve roots. Although the clinical presentation of acute segmental flaccid paralysis is rather unique, because WNV is a flavivirus, it is not surprising that the anterior horn region is affected.1 All flaviviruses of the Japanese and tick-borne encephalitis complex, including WNV, are known to affect lower motor neurons.8 –18 Of interest is that several the flaviviruses causes prominent facial, neck, and shoulder girdle weakness, best typified by Russian spring summer tick borne encephalitis.19 It therefore is reasonable to speculate that the paralysis of the patients described from Mississippi5 and Georgia6 as well as our cases are caused by anterior horn cell lesions, similar to that seen in acute poliomyelitis. One of our patients had an MRI showing abnormal signal intensity confined to the anterior horns, further supporting a role for spinal motor neurons in the pathogenesis of the disease. However, a potential involvement of ventral nerve roots and distal motor nerve fibers, as well, cannot be excluded. The rapidity of the paralysis also raises the possibility that damage to the anterior horn may be of vascular origin secondary to the meningeal inflammation. This is supported by inflammatory changes around vessels seen in the muscle biopsy of Patient 5 (see Fig 3). Interestingly, similar Li et al: Segmental Flaccid Paralysis 707 Table 3. Needle EMG Patient Muscle Fibs/⫹ Waves Motor Unit Case 1 L leg L lumbar paraspinal R leg L leg L lumbar paraspinal R leg L deltoid and biceps L triceps L abductor pollicis brevis L cervical paraspinal R arm L leg L orbicularis oris L arm L leg L cervical paraspinal R leg L leg R leg L arm L leg R arm R leg R lumbar paraspinal 0/1⫹ 2⫹/1⫹ 0/0 2⫹/3⫹ 0/1⫹ 0/1⫹ 2⫹/3⫹ 2⫹/1⫹ 2⫹/1⫹ 0/1⫹ 2⫹/3⫹ 1⫹/0 2⫹/4⫹ 2⫹/2–3⫹ 0/0–1⫹ 1⫹ 1⫹/1⫹ 0 0 3⫹ 1⫹ 3⫹/4⫹ 2⫹ N 3⫹ N N N 3⫹ N 1⫹ amp/dur 2⫹ poly N N 2⫹ 1⫹ 2⫹ 1⫹ N N 1 ⫹ Polyphasic N⫺ 2⫹ polyphasic N⫺ 1⫹ polyphasic 3–4⫹ N 3⫹ 2⫹ NA Unable to assess 1 Polyphasic N Polyphasic Polyphasic Polyphasic NA 2 4⫹ 2 2–3⫹ 2⫹ 2–3⫹ 3–4⫹ Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Recruitment Fig 2. Muscle and nerve biopsies: (upper left) Left lateral gastrocnemius muscle biopsy from Patient 1 shows scattered acutely necrotic myofibers (arrows) in early stage of phagocytosis. Frozen section, hematoxylin and eosin stain, ⫻250 original magnification. (upper right) Muscle biopsy from Patient 1. Detail of a necrotic fiber (arrow). Note absence of inflammation or endomysial fibrosis in surrounding muscle. Frozen section, hematoxylin and eosin stain, ⫻500 original magnification. (lower left) Left vastus lateralis muscle biopsy from Patient 2 shows scattered basophilic regenerating fibers (arrows) in distribution similar to Patient 1. Note absence of inflammation or fibrosis. Frozen section, hematoxylin and eosin stain, ⫻250 original magnification. (lower right) Crosssection of sural nerve biopsy from Patient 1 shows several degenerating fibers (arrows). Overall fiber density appears normal. No inflammation is noted. Plastic embedded section, toluidine blue stain, ⫻500 original magnification. 708 Annals of Neurology Vol 53 No 6 June 2003 Fig 3. Inflammatory changes in muscle biopsy. Left rectus femoris muscle biopsy from Patient 5 includes intramuscular nerve twig showing inflammation of small endoneurial and perineurial blood vessels (long arrows) and scattered degenerating myelinated nerve fibers (short arrows). There were perivascular cuffs of mononuclear inflammatory cells around the vessels, and some of the inflammatory cells may have infiltrated the vessel wells. Because the small size of the vessel, we could not be certain whether vessel walls were necrotized. Frozen section, hematoxylin and eosin stain, ⫻500 original magnification. inflammatory changes have been described in other flavivirus infections.20 The histological findings from muscle biopsies are intriguing. Scattered, necrotic muscle fibers are an unlikely explanation for the severe paralysis observed. The presence of these necrotic muscle fibers raises the possibility of viral invasion of muscle. However, immunohistochemistry did not detect WNV on biopsied muscle. Because the immunohistochemistry was performed in only one case, the possibility of direct viral invasion to muscles cannot be completely excluded at this time. We observed prolonged distal motor latencies and F-wave latencies in at least two patients (see Table 2), implying that there may be a demyelinating component. However, this slowing might be exaggerated by the low amplitudes of the compound muscle action potential and ventral nerve root damage. Moreover, the inflammatory infiltration identified in the terminal twigs of motor nerves (see Fig 3) may contribute to the prolongation of distal motor latencies. Interestingly, there was a recent case report documenting an acute inflammatory demyelinating polyneuropathy–like presentation in a WNV infection patient with CVs of approximately 20 to 30 meter/second.21 These are well below the CVs we observed. 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