Concurrent Acute Motor and Sensory Axonal Neuropathy and Immune Thrombocytopenic Purpura

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1 MILITARY MEDICINE, 178, 3:e367, 2013 Concurrent Acute Motor and Sensory Axonal Neuropathy and Immune Thrombocytopenic Purpura CPT Ian M. Ward, MC USA*; CPT Allyson E. Fewell, MC USA*; CPT David M. Ferraro, MC USA ; COL Michael J. Morris, MC USA (Ret.) ABSTRACT Background: Guillain Barré syndrome (GBS) is a potentially life-threatening autoimmune disease causing demyelination of peripheral nerves. Multiple variants of GBS exist, with acute motor and sensory axonal neuropathy (AMSAN) being the most severe. GBS typically does not occur in the setting of other autoimmune diseases; however, few case reports do exist describing the occurrence. Methods: We describe a patient with acute motor and sensory deficits and thrombocytopenia, ultimately diagnosed with concurrent AMSAN and immune thrombocytopenic purpura (ITP). Results: A 75-year-old woman presented with new onset diplopia and gait instability, however, was found to have a severe thrombocytopenia. Corticosteroids were initiated for ITP and intravenous immunoglobulin for apparent GBS. Nerve conduction studies and her clinical course indicated that she likely had AMSAN. Although her platelet count recovered, her neurologic status remained poor, prompting therapy with plasmapheresis with subsequent mild improvement. Conclusion: A review of the literature revealed eleven previous cases of concurrent GBS and ITP; however, we report the first case of concurrent AMSAN and ITP. Among these cases, trends were noted to include sex, preceding infections, and cranial nerve involvement. INTRODUCTION Guillain Barré syndrome (GBS) is a well-described autoimmune disease affecting the peripheral nerves, presenting as an acute neuropathy characterized by muscular weakness, diminished or absent reflexes, and occasionally sensory disturbances. Several variants of the disease exist with the most common form being acute inflammatory demyelinating polyradiculoneuropathy, a T-cell-mediated macrophageinduced demyelination of peripheral nerves. Accounting for less than 5% of all GBS cases, the other variants are characterized by B-cell-mediated macrophage-induced destruction of the nodes of Ranvier, causing complete denervation and block of nerve conduction. 1 The most severe variant is acute motor and sensory axonal neuropathy (AMSAN), distinguished by fulminant and rapid onset of quadriparesis within 7 days of onset of symptoms, usually requiring prolonged respiratory support. 2 Unlike many other autoimmune diseases, GBS tends to develop in patients without other concurrent autoimmune diseases. Despite the rare occurrence of simultaneous GBS and other autoimmune diseases, we report a patient with rapid onset neurologic dysfunction and impending respiratory failure with a severe thrombocytopenia, ultimately diagnosed with AMSAN and concurrent immune thrombocytopenic purpura (ITP). *Internal Medicine Residency, Department of Medicine, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, TX Pulmonary/Critical Care Service, Department of Medicine, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, TX doi: /MILMED-D CASE REPORT A 75-year-old Caucasian woman presented to our institution complaining of a 10-day history of upper respiratory symptoms and new onset double vision. She likewise reported malaise and mild gait instability of several days, prompting use of her husband s walker. The patient was afebrile, in no acute distress, with a respiratory rate of 20 and an oxygen saturation of 99% on room air. Her initial examination revealed multiple neurologic findings to include a bilateral cranial nerve VI (abducens) palsy, gait instability, areflexia, and decreased vibratory sensation in the lower extremities. No motor deficits or weakness were noted on the initial neurologic examination. A complete blood count showed a normal hematocrit, hemoglobin, and white blood cell count; however, the platelet count was decreased at 20,000/mm 3.Electrolytes, renal function, thyroid function, and hepatic function studies were all within normal limits. Both the erythrocyte sedimentation rate and the C-reactive protein level were elevated at 73 mm/s and 14.5, respectively. A computed tomography scan of the head was unremarkable without hemorrhage or mass lesion. She was admitted to the medical intensive care unit because of the presence of severe thrombocytopenia and neurologic dysfunction. Subsequent examinations over the next 12 hours showed progression with development of complete ophthalmoparesis, dysarthria, bilateral upper and lower extremity paresthesias, and diffuse motor weakness. Because of a negative inspiratory force of 10 cm H 2 O, she was intubated and placed on mechanical ventilation. Based on the clinical findings of progressive neurologic dysfunction and recent respiratory illness, her clinical presentation was consistent with GBS. As a practicing Jehovah s Witness, the patient and her family initially declined both plasmapheresis and intravenous immunoglobulin (IVIG) for religious reasons. Repeat complete blood count continued to show a severe thrombocytopenia with the platelet count decreasing to 9,000/mm 3. Review of the peripheral smear was consistent with a true thrombocytopenia without e367

2 platelet clumping, schistocytes, or other abnormal cells. Methylprednisolone 1 g every 24 hours was initiated for treatment of ITP with planned therapy for 5 days. After further discussions with the family about her GBS and treatment options, the patient and family agreed to the use of IVIG, which began at 400 mg/ kg/day on hospital day 2. They continued to object to plasmapheresis due to the requirement for albumin that was strictly forbidden because of their religious beliefs. Test results for Lyme, rapid plasma reagin, human immunodeficiency virus, mycoplasma, West Nile, and botulinism titers were negative, as were titers for neurologic conditions to include myasthenia gravis, Eaton Lambert, and paraneoplastic and anti-ganglioside antibodies. Result for rapid influenza A enzyme-linked assay was positive. Further test results for Campylobacter jejuni, Helicobacter pylori, cytomegalovirus, and Epstein Barr virus were also positive, but these studies were acquired after initiation of IVIG. A nerve conduction study (NCS) was performed on hospital day 4 (Fig. 1), showing electrically unexcitable motor and sensory nerves, suggesting a rare variant of GBS termed AMSAN (Tables I and II). Because of the continued low platelet count of the patient, lumbar puncture was deferred until hospital day 8, at which time it was performed with fluoroscopic guidance. The cerebrospinal fluid revealed an albumin/cytologic disassociation, with a leukocyte count of 1 cell per high-powered field and a protein level of 101 mg/dl, providing further evidence supporting the diagnosis of GBS (Fig. 1). The platelet count of the patient recovered during the next 2 weeks after a 5-day treatment with IVIG and tapering doses of methylprednisolone. However, there was no improvement in her neurologic function beyond maintaining motor function of her left great toe. Electromyography was performed on hospital day 15, which exhibited complete loss of motor unit stimulation diffusely, consistent with an axonal polyneuropathy, specifically AMSAN. Because of lack of clinical response, she was transferred on hospital day 27 to a nearby military treatment unit with the facility to perform plasmapheresis using hetastarch as a volume expander and avoid using human blood products. She underwent ten plasmapheresis treatments; by hospital day 36, she began to have mild neurologic recovery, regaining some motor function of her left foot, ankle, ocular muscles, and sensation to face and FIGURE 1. NCSs provide key information on the type of nerve involvement as well as the mechanism of the nerve damage. (A) Patient s left tibial nerve EMG with ankle (A1) and popliteal fossa (A2). (B) Patient s left ulnar nerve (A1) and left median nerve (B2) sensory NCS. e368

3 TABLE I. Motor NCS Values, Case and Normal Nerve Site Latency (milliseconds) Amplitude ( mv) Conduction Velocity (m/s) Case Motor NCS Values Median (Left) No Response No Response No Response Ulnar (Right) Wrist Below Elbow Peroneal (Left) Tibialis Anterior No Response No Response No Response Extensor Digitalis Brevus Ankle Fibula (Head) Popliteal Fossa Tibial (Left) Ankle Popliteal Fossa No Response No Response No Response Normal Motor NCS Values Median <4.2 >4.4 >49 Ulnar <3.4 >6.0 >49 Peroneal Tibialis Anterior <3.0 >5.0 >42 Extensor Digitalis Brevus <5.8 >2.0 >42 Tibial <6.5 >3.0 >41 Normal values derived from Adams and Victor s Principles of Neurology. 3 upper extremities. With completion of her plasmapheresis, mild neurologic improvement, and stable platelet count, she was transferred to a long-term acute care facility for further management and rehabilitation. DISCUSSION AMSAN is the most severe variant of GBS as it causes axonal denervation of both the ventral and the dorsal nerve roots and carries the worst recovery prognosis. Like the other GBS variants, AMSAN is a B-cell-mediated macrophageinduced demyelinating disease that affects both the ventral and the dorsal horns, thereby causing both motor and sensory deficits. 1 Cases of AMSAN are rare, and no previous cases have been reported of both AMSAN and another concurrent autoimmune disease. The patient we described had a very typical presentation for AMSAN, but was also noted to have thrombocytopenia, ultimately diagnosed as ITP. Characterized TABLE II. Nerve Site Sensory NCS Values, Case and Normal Latency, Onset/Peak (milliseconds) Amplitude (mv) Conduction Velocity (m/s) Case Sensory NCS Values Median (Left) No Response No Response No Response Ulnar (Left) No Response No Response No Response Radial (Left) No Response No Response No Response Sural (Left) No Response No Response No Response Normal Sensory NCS Values Median <2.5/<3.5 >20 >52 Ulnar <2.1/<3.0 >15 >52 Radial <1.9/<2.8 >20 >48 Sural <3.2/<4.4 >6 >42 Normal values derived from Adams and Victor s Principles of Neurology. 3 by autoimmune destruction of platelets, ITP is diagnosed by a platelet count less than 100,000/mm 3 in the absence of other processes that could lead to a thrombocytopenia. The diagnosis is made by excluding other causes of thrombocytopenia as no diagnostic test exists to confirm ITP. 4 As with many autoimmune phenomena, it is believed that an immune response prompted by a preceding infection crossreacts with self-antigens, leading to the development of the autoimmune response damaging the peripheral nerves. The antibodies associated with the variants of GBS are directed against gangliosides specifically found in the makeup of myelin. 1 Gangliosides are also found in platelets; however, those gangliosides do not correlate with the gangliosides found in the nervous system. 5 Instead, ITP is characterized by an autoimmune reaction against the glycoproteins GPIIa-IIIb or GPIb- IX. Although the autoimmune reaction is usually targeting the glycoproteins of platelets in circulation, an autoimmune process also occurs in the bone marrow, causing decreased production of platelets by the megakaryocytes. 6 No overlapping antigen has been discovered between GBS and ITP. Many different inciting infections have been described as causing both GBS and ITP, with the most common being Epstein Barr virus, cytomegalovirus virus, influenza, Mycoplasma pneumoniae, and human immunodeficiency virus. 1,2,4,5 In particular, C. jejuni has been associated with GBS, 1 whereas H. pylori has been implicated in ITP. 4 In this patient, it was noted during her workup that she had previous upper respiratory symptoms and was found to be influenza A positive, possibly providing the inciting insult that lead to the development of her diseases. Management of all variants of GBS includes either IVIG or plasmapheresis; treatment is supported by a Cochrane Review showing no difference between the two therapies in improvement of disability after 4 weeks. 7 TheAmericanAcademyof Neurology practice parameter affirmed the results of the e369

4 TABLE III. Characteristics of Patients With Concurrent GBS and ITP Age/Sex Preceding Infection GBS Variant Cranial Nerve Involvement Treatment 30/F 11 URI AIDP CN VII Steroids 32/F 12 Rubella AIDP None Steroids, IVIG, Imuran 3/F 13 URI Unknown CN VII + IX Unknown 75/F 14 URI AIDP None Steroids 50/F 15 Unknown Unknown CN VII Steroids 50/F 16 URI AIDP CN III Steroids, IVIG 73/M 17 Unknown AIDP CN VII IVIG 67/M 5 URI AIDP None Steroids, IVIG 17/F 18 URI AIDP CN VII + IX Steroids, IVIG 21/F 19 URI/EBV/CMV Unknown None Steroids, IVIG, Rituxan, AntiD 51/M 20 URI Fisher Variant CN VII None 75/F URI AMSAN CN III, IV, + VI Steroids, IVIG, Plasmapheresis Adapted from Sato et al. 5 Cochrane Review stating that either IVIG or plasmapheresis were acceptable first-line therapies for GBS. Corticosteroids had no role in treating GBS. Of note, despite the proposed B-cell-mediated pathogenesis of AMSAN and the other GBS variants, rituximab is not part of the recommended first- or second-line therapies in the treatment of acute GBS. 8 Close surveillance is needed in patients with GBS as respiratory depression and failure can occur as a result of diaphragmatic paralysis. A forced vital capacity less than 15 to 20 ml/kg, negative inspiratory force less than 30 cm H 2 O, and/or maximal expiratory pressure less than 40 cm H 2 O are considered criteria for elective intubation as the patient is nearing respiratory failure. 9 Immune thrombocytopenia, as recommended by the American Society of Hematology, should be treated with either corticosteroids or IVIG, both as first-line therapies. However, treatment is not always needed as some cases may spontaneously remit. Therapy is generally reserved for patients with platelet counts less than 30,000/mm 3. 4 GBS and ITP are both relatively common autoimmune conditions, each occurring at a rate of less than five cases per 100,000 patients annually. 1,10 Autoimmune conditions often appear to occur concurrently, and ITP often occurs with other autoimmune diseases 4 ; however, GBS typically does not occur with other autoimmune diseases 11 and the concomitant occurrence of GBS and ITP is extremely rare. Sato et al 5 reported in 2005 a compilation of seven published cases in addition to their case of concurrent GBS and ITP. Our updated review of the literature revealed that eleven previous cases of concurrent GBS and ITP have been reported (Table III). Of these eleven, seven were the acute inflammatory demyelinating polyradiculoneuropathy variants of GBS, three had unreported variants of GBS, and one was the Miller Fisher variant. No NCS proven AMSAN variants have been reported to occur concurrently with ITP to date, making this potentially the first such case. A review of the cases showed multiple trends among the patients. The majority (73%) were female, had a preceding upper respiratory infection reported (73%), and had early cranial nerve involvement (64%). None of these patients had a preceding gastrointestinal infection, which is the classic preceding infection for GBS. Our patient followed the pattern of patients with concurrent GBS and ITP, as manifested by an elderly female with early cranial nerve involvement, recent upper respiratory infection, and no preceding diarrheal illness. These associations may provide a clue in determining a linking antigen that predisposes to developing concurrent GBS and ITP. This patient s diagnosis of AMSAN carried a poor prognosis for recovery despite the multiple medical interventions made during her hospitalization to treat the autoimmune process. Our review of the literature supports that this case is unique as the first reported case of a GBS variant, AMSAN, with ITP. The previously reported cases of GBS and ITP exhibited several similarities to our patient, underlining the conclusion that each of these previous patients likely developed cross-reactivity against both platelet and neurogenic glycoproteins following an antecedent infection. This case emphasizes the treatment decisions related to the finding of concurrent GBS and ITP. REFERENCES 1. Hughes RA, Cornblath DR: Guillain-Barré syndrome. Lancet 2005; 366: Harati Y, Bosch EP: Disorders of peripheral nerves. In: Bradley: Neurology in Clinical Practice, Ed 5, Vol. 2, pp Edited by Bradley WG, Daroff RB, Fenichel GM, Jankovic J. Philadelphia, Butterworth-Heinemann Elsevier, Ropper AH, Samuels MA: Electrophysiologic and laboratory aids in the diagnosis of neuromuscular disease. In: Adams and Victor s Principles of Neurology, Ed 9, pp Edited by Sydor AM, Davis KJ. 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