Non-Hodgkin Lymphoma and Guillain-Barré Syndrome: A Rare Association
1Department of Internal Medicine, South West General Hospital, University Hospitals of Cleveland, Cleveland, Ohio; 2Department of Internal Medicine, Cleveland Clinic Cancer Center, Fairview Hospital, Cleveland, Ohio
Firas Seffo, MD1
Hamed A. Daw, MD2
Introduction
Non-Hodgkin lymphoma (NHL) is a neoplastic transformation of cells that reside predominantly within lymphoid tissues, which may be of B- or T-cell origin. There is a slight male-to-female predominance and a higher incidence in whites than blacks.
Incidence rises steadily with age, especially after 40 years. Extranodal lymphomas usually present as a mass, and sometimes as a fever of unknown origin. Primary central nervous system involvement results in headaches, seizures, lethargy, focal neurologic symptoms, or paralysis. Uncommon initial presentations of NHL include spinal cord compression and lymphomatous meningitis. Peripheral nervous system abnormalities occur in 5% of patients with lymphoma and have a wide differential diagnosis, with herpes zoster being the most common cause.1 Direct lymphomatous involvement of the peripheral nerves (neuro- lymphomatosis) is a rare event, often occurring in the presence of widespread systemic disease.2 Peripheral neuropathy is commonly attributed to the toxic effect of chemotherapeutic agents.3,4 Another cause of central nervous system damage is radiation myelopathy. Paraneoplastic neurologic syndromes, such as Guillain-Barré syndrome (GBS), are rare in NHL.5,6 We describe a rare case of NHL complicated by GBS.
Case Report
A 70-year-old, white, right-handed woman complained of bilateral leg weakness 3 weeks after her sixth cycle of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy for NHL. She gradually developed progressive bilateral leg weakness and had to use a wheelchair. She complained of some back pain, but denied any numbness or tingling in her legs, bladder or bowel dysfunction, or any shooting or radiating pains.
Four months prior, the patient had presented with left nasal mass infiltrating the left orbit and was diagnosed with T/NK-cell NHL, nasal type, stage Ie-A. She was treated with 6 cycles of CHOP and was in complete remission with total regression of the tumor 4 cycles into treatment. She also had hypertension, hyperlipidemia, anemia due to CHOP requiring blood transfusion, and anxiety disorder. Home medications included atenolol, atorvastatin, aspirin, bupropion hydrochloride, trazodone, multivitamins, propoxyphen, and zolpidem tartrate. The patient had quit smoking 30 years prior and denied alcohol or drug abuse. She had no other systemic symptoms. On exam, she was afebrile, with blood pressure of 108/66 mm Hg, heart rate of 80 beats per minute, respiration of 16 breaths per minute, weight of 128 pounds, and height of 5 feet, 6 inches. The head, ears, eyes, nose, and throat exam revealed no lymphadenopathy in the head, neck, or supraclavicular fossa, and no thyromegaly. The chest was clear to auscultation bilaterally, and the heart had regular rate and rhythm. The abdomen was soft and nontender to palpation, and bowel sounds were normoactive. No hepatosplenomegaly or masses were observed. No pitting edema, cyanosis, or clubbing were seen on the extremities. No percussion tenderness was seen when the back was checked. The neurologic examination revealed an alert and oriented (×3) mental status. Cranial nerve examination revealed normal visual fields; the fundi were grossly normal, and the pupils were normal. Pursuit eye movement testing uncovered left adductor limitation leading to a diplopia. Facial sensation was normal.
There was a slightly diminished left nasolabial fold. Hearing, palatal movement, pronation, resonation, strength in trapezius, sternocleidomastoid, and tongue protrusion were normal. The motor exam revealed finger abduction 5 of 5 bilaterally, triceps 5 bilaterally, and deltoid 5 bilaterally, and toe flexion 5 bilaterally, toe and ankle dorsiflexion 5 right, 0 to 1 left, and plantar flexion 5 bilaterally. Ankle eversion was 5 right, absent left, and ankle inversion 5 right, 3 left. Knee flexion was 4 right, 2 left, and knee extension was 3 right, 3 left. Hip flexion was 3 bilaterally. Hip was adduction 3 bilaterally, and hip abduction 3 to 4 bilaterally. Tone, bulk, and posture were normal. There were no fasciculations, abnormal movements, or asterixis. Sensory exam showed that pain was diminished in the dorsums of the feet and lateral calves bilaterally. Vibration was diminished in both great toes and joint position, and sensation was diminished at the right great toe and absent in the left great toe. The patient had a loss of the left dorsiflexor phase with toe wrinkling and rapid alternating movements that were otherwise normal. Finger-to-nose was normal bilaterally, but gait was not tested due to profound weakness in the legs. Deep tendon reflexes were 2- left triceps and absent at the right triceps; both biceps, both knees, and both ankle jerks were absent. The plantars were equivocal bilaterally. Diagnostic data revealed serum calcium of 9.5 mg/dL, sodium of 138 mmol/L, normal serum vitamin B12 level >2000 pg/mL, hematocrit of 27%, platelet count 198 x 109/L, and creatinine 0.8 mg/dL. Magnetic resonance imaging (MRI) of the lumbosacral spine was unremarkable. Lumbar puncture revealed clear, colorless fluid; the opening pressure was 162 mm of water. Cerebrospinal fluid (CSF) examination exposed elevated protein (81 mg/dL), glucose 44 mM, and white blood cell count of 11 × 109 cells per liter, mostly lymphocytes. Electromyography demonstrated bilateral acute sensory motor polyneuropathy compatible with GBS. The patient developed quadriparesis, neurogenic bladder, neurogenic bowel, and right facial nerve palsy despite treatment, and was discharged to hospice.
Discussion
GBS is an idiopathic acute inflammatory demyelinating polyneuropathy that is believed to be immunologically mediated. Approximately two-thirds of the cases are related to a recent upper respiratory or gastrointestinal tract infection, especially infections due to Campylobacter jejuni, Cytomegalovirus, and Epstein-Barr virus.7 Recent immunization has also been associated with GBS. The swine influenza vaccine, administered widely in the United States in 1976, is the most notable example; the mechanism is presumably immunization against neural antigens. GBS has been reported to be associated with some systemic diseases such as Hodgkin lymphoma, HIV, and systemic lupus erythematosis.8,9 It is extremely rare in NHL, occurring in less than 0.3% of cases.10 Table 1 summarizes the common causes of GBS.
GBS is manifested as an acute, ascending polyneuropathy, predominantly motor paralysis with respiratory failure, leading to death. In severe cases, the ocular motor nerves are involved and even the pupils may be unreactive. More than half of the patients complain of pain and an aching discomfort in the muscles—mainly those of the hips, thighs, and back—and therefore can be misdiagnosed with lumbar disc disease, back strain, and other orthopedic diseases. Sensory loss occurs to a variable degree during the first few days and may be barely detectable. Reduced and then absent deep tendon reflexes are consistent findings. The most important diagnostic studies are electromyography (EMG) and CSF examination. The CSF is under normal pressure and is acellular or contains only a few lymphocytes and 10–50 cells per mL at most, whereas protein levels are elevated (albuminocytologic dissociation, elevated proteins without cells). Abnormalities of nerve conduction are early and dependable diagnostic indicators of GBS. The most frequent early electrodiagnostic findings are reduction in the amplitude of muscle action potentials, slowed conduction velocity, and conduction block in motor nerves. Prolonged distal latencies (reflecting distal conduction block) and prolonged or absent F-responses (indicating involvement of proximal parts of nerves and roots) are other important diagnostic findings, all reflecting focal demyelination. Table 2 illustrates the diagnostic criteria for GBS.
Most peripheral neuropathies in NHL are attributed to local infiltration by lymphomatous cells causing axonal damage.5 This disorder can affect nerve roots and cranial nerves, often associated with lymphomatous meningitis. NHL may also infiltrate peripheral nerves and causes plexopathy, mononeuropathy, or generalized neuropathy. These neuropathies may resemble an asymmetric mononeuropathy multiplex or a generalized disorder such as chronic inflammatory demyelinating polyradiculoneuropathy. When NHL infiltrates diffusely, the term neurolymphomatosis is used. The initial differential diagnosis in our patient included cauda equina syndrome (which was excluded by the findings of MRI of the lumbosacral spine), chemotherapy drug toxicity (which could not explain her areflexia), lymphomatous (carcinomatous) meningitis, intramedullary lymphoma of the spinal cord, epidural compression of the cervical and thoracic cord, metastasis to the falx cerebri with involvement of the foramen magnum by affecting the leg decussation but not the arm decussation (rare possibility), and demyelinating neuropathy as a paraneoplastic entity (GBS). The presentation was more suggestive of a rapidly progressive entity such as cord compression (excluded by MRI) or a demyelinating polyneuropathy and was confirmed by the finding of cytoalbuminologic dissociation on CSF examination.
Conclusion
We believe that immune mechanisms triggered by NHL initiated the development of GBS in this patient. Although GBS is commonly seen in Hodgkin lymphoma, it is an extremely rare entity in NHL. Our literature review revealed some case reports of GBS associated with B-cell lymphoma and Burkitt lymphoma,5,6,7,10 but we believe that this is the first report of T/NK-cell lymphoma, nasal type associated with GBS.
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