A 61-year-old man African American with a history of diabetes mellitus type 2 and hypertension presented to our clinic with acute dysphagia, proximal limb-girdle weakness, and dermatitis. Dysphagia began two days prior to admission, which was initially described as a “tickling and grabbing” sensation that rapidly progressed to severe dysphagia associated with odynophagia. Symmetric proximal weakness predominantly in limb-girdle distribution initially began as weakness with stair climbing and running followed by fasciculation in the thighs and upper arms with fairly rapid progression to inability to stand or squat independently over the course of two months. A rash appeared acutely at the same time as weakness and lethargy, initially affecting the face bifrontally with progression to the entire face, upper torso, and extensor surfaces of the lower extremities eventually becoming confluent.
Physical examination was significant for moderate symmetric proximal weakness of the arms with inability to lift arms above his head. Asymmetric weakness of the legs was present with the right affected more than the left and in both proximal and distal distributions. Fasciculation was apparent in the arms and legs consistent with the distribution of weakness. Asymmetric atrophy was noted predominantly in the legs with midthigh diameters of 39.5 cm on the right and 44.0 cm on the left. Deep tendon reflexes were 1+ in the arms and legs. A macular, nonerythematous skin rash was observed on scalp, face, torso, and extensor surfaces of the limbs.
The patient didn’t smoke previously and drinks alcohol socially. He had no history of drug abuse or recent vaccination. His medications included metformin, lansoprazole, Repaglinide, telmisartan, and prednisone, which was started one week prior to the admission for dermatitis.
Complete blood count showed a total white blood cell (WBC) count of 14,600/mm3. Granulocytes comprised 75% and lymphocytes 15% of total leukocytes with an absolute lymphocyte count of 2100/mm3. Hemoglobin was 11.4 mg/dL with a mean corpuscular volume (MCV) of 94 and a platelet count of 165,000/mm3. Metabolic profile was unremarkable except for an albumin of 2.0 mg/dL and aspartate aminotransferase of 74 mg/dL. Serum creatine phosphokinase level was mildly elevated at 1056 mg/dL.
Initial electrodiagnostic studies revealed nerve conduction consistent with mild length-dependent sensorimotor neuropathy with mixed axonal and demyelinating features. Electromyography revealed denervation potentials and short duration, small amplitude motor units with prominent polyphasia and early recruitment, suggestive of a myopathic process affecting proximal muscles. Subsequent follow-up electrodiagnostic studies over the next month showed progression to widespread denervation with similar myopathic motor unit action potentials with mixed early and reduced recruitment. Serologic studies for autoimmune diseases were negative (eg, rheumatoid factor, RNP antibodies, anti SCL70, anti-Smith, SSA, SSB, anti-ds DNA, smooth muscle antibodies). Serum complement levels were also within normal limits. Genetic testing for survival motor gene (SMN1), androgen receptor CAG repeat expansion, and hexoaminidase deficiency was negative. Serologic testing for GM1 ganglioside autoantibodies was negative. Heavy metal screening for lead, arsenic, and mercury exposure was negative as well. Paraneoplastic antibody screening was negative (eg, anti-Hu, anti-Yo, voltage-gated calcium channel, and anti-Jo antibodies).
A skin biopsy showed superficial perivascular lymphocytic infiltrates with subepidermal neutrophilic infiltrates. Muscle biopsy of the right vastus lateralis revealed two patterns of muscle abnormality. Discrete areas of severe interstitial fibrosis and fatty replacement were juxtaposed to areas of nearly intact muscle (; Trichrome stain, low magnification). Adenosine Triphosphatase stain showed prominent fiber-type grouping in the areas with preserved fibers (), consistent with a chronic neuropathic pattern of denervation with reinnervation. There was no significant endomysial, perimysial, or perivascular inflammation, and no findings diagnostic of an underlying specific myopathic or dystrophic process.
Trichrome stain showing portion of well-preserved muscle (upper left), and an area of markedly atrophic muscle, with extensive fibrosis (lower right).
ATP-ase stain showing loss of normal checker-board pattern of muscle fibers, with large groups of type I and type II fibers, diagnostic of denervation/reinnervation.
Magnetic resonance imaging (1.5 Tesla) with intravenous gadolinium diethylenetriaminepentaacetic acid of the neuroaxis revealed chronic mild microvascular ischemic changes in the brain, multilevel degenerative disk disease in the cervical and lumbosacral segments with varying levels of spinal canal and neuroforaminal stenosis. No enhancement of the neuroaxis or nerve roots was seen. Computed tomography with contrast of the chest, abdomen and pelvis revealed few small pulmonary nodules up to 5 mm in size without any evidence of underlying malignancy in the thorax or intraabdominally. Positron emission tomography (FDG-PET w/10.2 mCi 18-fluorine) of the whole body did not reveal any areas of abnormal uptake.
The patient was started on high-dose corticosteroids (prednisone) after initial evaluation for presumed inflammatory myopathy prior to biopsy results with dramatic improvement in the skin lesions and the proximal muscle strength to the point where he was able to stand and walk independently. Despite improvements in limb strength, bulbar symptoms continued to decline to the point where he was intubated for several days due to aspiration. He was subsequently extubated and had percutaneous gastrostomy placed due to severe dysphagia. Macular rash progressed to affect the entire chest, back and flexor surfaces of the limbs both proximal and distal associated with some induration. At that time, patient refused further diagnostic investigation including bone marrow biopsy. After initial response to steroids, limb weakness progressed with subsequent development of atrophy in both proximal and distal muscles. He was eventually started on intravenous immunoglobulin with minimal improvement after 1 month.
At that point it was decided to do a bone marrow biopsy because of anemia and slightly elevated MCV of 103. The examination of the bone marrow biopsy revealed small interstitial lymphoid aggregate (). The cells within the aggregate were composed of monomorphous small lymphocytes with scant pale cytoplasm and condensed chromatin (). Most significantly, the immunophenotype of the lymphoid aggregate expressed CD5 (), CD20 (), and CD23 (), positivity, which was consistent with CLL immunophenotype. Flow cytometry demonstrated monoclonal CD5/CD19-positive cells, CD20 (dim), CD23-positive, kappa (dim), FMC-7-negative, and CD3-negative. It was positive for ZAP 70 and chromosomal analysis showed trisomy 12.
A small interstitial lymphoid aggregate is identified (magnification, 100×).
Monomorphous small lymphocytes with scant pale cytoplasm and condensed chromatin (magnification, 400×).
CD5 positivity (magnification, 400×).
CD20 positivity (magnification, 400×).
CD23 positivity (magnification, 400×).
As the absolute lymphocyte count at that time was under 5000/mm3 and there was no lymphadenopathy visible on the imaging, he did not meet the criteria for CLL/small lymphocytic lymphoma. However, considering the possibility of paraneoplastic phenomenon for his symptoms, a diagnosis of CLL in this patient is made with clinical and pathologic correlation. Patient was started on CLL-directed therapy with Rituximab 375 mg/m2 and Cyclophosphamide 1000 mg/m2. After only two cycles, the patient experienced a dramatic improvement in his symptoms. The muscle strength and swallowing improved significantly. Also, we noticed disappearance of his skin rash which had persisted despite previous treatment with topical and systemic steroids. The patient was able to swallow and subsequently his percutaneous endoscopic gastrostomy tube was removed. The patient completed six cycles of chemotherapy and at the end of therapy he was able to stand, squat, and walk independently with marked improvement in strength both proximally and distally.