A 78-year-old Caucasian man presented to our hospital with a history of weakness in the left arm and shoulder, with discomfort and difficulty dressing himself, for the past one and a half months. Initially he had attributed his issues to a prior rotator cuff injury. He then noted progressive shrinking in the muscles of his left arm and hand with decreased grip strength (overall he felt that he lost about 80% strength in his left arm) and developed uncomfortable 'charley horses' (painful spasms or cramps) in his left leg. There were no sensory, swallowing, or visual issues, and he denied having experienced any head or neck trauma. His medical history was significant for hypertension, coronary artery disease, hypercholesterolemia, hypothyroidism, and peptic ulcer disease.
Results of a neurological examination showed atrophy in the left biceps and deltoid and also the left first dorsal interossei (DI) muscle. Fasiculations were noted in the left forearm and left first dorsal interossei. Strength testing results, using Medical Research Council (MRC) grades, were as follows: left biceps 4/5, deltoid 4/5, and diminished grip strength 4/5. Strength testing in the left abductor digiti minimi (ADM) was 5-/5, left flexor digitorum profundus (FDP) 1 and 2 was 5-/5, left extensor carpi radialis longus (ECRL) 4+/5, and 4/5 in the left infraspinatous. Diminished grip strength (4/5) of the left hand was also noted. Normal strength testing (5/5) was noted in the right arm and bilateral lower extremities. Deep tendon reflexes were 1/4 in the left brachioradialis, biceps, and triceps and 2/4 for others. His toes were downgoing bilaterally. A mild gait imbalance was observed. His sensory examination was completely intact. No coordination deficits were seen. No cranial nerve deficits were observed except for mild tongue fasciculations. His speech was fluent without dysarthria or dysphasia.
An electrodiagnostic study performed the same week showed low amplitudes in the left upper extremity motor nerve compound muscle action potentials with intact sensory nerve action potential responses. There was no evidence of any abnormal temporal dispersion or conduction block in multiple nerves tested. There were 1-2+ fibrillation potentials and positive sharp waves in the left deltoid, triceps, biceps, flexor carpi radialis (FCR), first DI, tibialis anterior, and bilateral gastrocnemius medial heads. His tongue showed a discrete firing pattern without abnormal resting activity.
The results of neuroimaging studies of the spine revealed age-related degenerative joint and disc disease with spondylosis, but nothing that was felt would account for his clinical condition. The working diagnosis at this point was motor neuron disease (MND) probably secondary to ALS (or 'clinically possible ALS', via El Escorial criteria).
Further laboratory investigations revealed a monoclonal gammopathy (IgGλ subtype) (2,019 mg/dL, with the normal range being 694 to 1618 mg/dL) (κ to λ ratio of 1:2, with the normal ratio being 2:1) via both serum protein electrophoresis and serum immunofixation with leukopenia and anemia (moderate normochromic normocytic) along with B12 deficiency (116 pg/ml). Homocysteine was elevated (43.2 μmol/L, with the normal level being <11.4 μmol/L). Parietal antibody test results were positive (1:80, with normal results being <1:20) and an intrinsic factor antibody test result was positive, and for these reasons it was felt that our patient was B12 deficient. His erythrocyte sedimentation rate (ESR) was slightly elevated at 40 mm/hour (the normal range being within 0 to 20 mm/hour) but an anti-nuclear antibody screen test result was negative. It was therefore felt that the elevated ESR was due to anemia and/or monoclonal gammopathy rather than an underlying autoimmune process. Motor and sensory neuropathy panels and paraneoplastic panel test results were negative.
In order to exclude any potentially treatable causes of MND, our patient underwent a bone marrow biopsy to exclude any plasma cell dyscrasia. The results showed hypocellular marrow with a hematopoietic cellularity of 20-40% (overall 30%) with no evidence of any granuloma or lymphoma, or tumor. Immunophenotyping data did not show any evidence of neoplasia. There was no evidence of any myeloproliferative disorder. Our patient also underwent a colonoscopy, which showed multiple polyps but no evidence of any tumor. Our patient was given B12 supplements via injection by a hematologist, with a diagnosis of monoclonal gammopathy of undetermined significance (MGUS), B12 deficiency, and pernicious anemia.
Our patient's symptoms progressed to weakness in the left shoulder with increasing weakness in the left arm, and he underwent subsequent re-evaluation at a local university neuromuscular department approximately 2 months later. The re-examination showed atrophy in the bilateral spinati (left > right) along with persistent atrophy in the left first DI, left thenar, and left deltoid and biceps. Strength testing showed deltoid less than antigravity with 4-/5 biceps, 4-/5 triceps, and wrist extensors less than gravity on the left side with an inability to extend the fingers. Wrist flexion and finger flexion results were 4+/5 and interossei 3/5. In the right upper extremity the thenar group was 4-/5, infraspinatous 4/5, supraspinatous 4/5, deltoid 5-/5, biceps 5-/5, and the pectoralis 4-/5. The forearm muscles and hand muscles on the right side were in the 4+ to 5- range. Fasiculations were noted in the upper extremity muscles in a scattered distribution, predominately proximally.
A repeat electrodiagnostic study preformed approximately three to four weeks later revealed active denervation in multiple myotomes in both the upper and lower extremities with chronic denervation. Motor axonal loss changes were noted without conduction block.
Further laboratory test results that week included the following: parathyroid hormone (PTH) was elevated (155 pg/mL, normal range 10 to 65 pg/mL) and the calcium level was normal (9.6 mg/dL, normal range 8.8 to 10.3 mg/dL). Our patient's renal function was normal. Unfortunately, 25-hydroxy vitamin D levels were not tested.
The university diagnosis at that time was 'motor neuron disease confounded by monoclonal gammopathy and possible hyperparathyroidism'. This corresponded with the El Escorial criteria classification of 'clinically probable laboratory supported ALS'. A trial of intravenous immunoglobulin was considered for our patient, but not recommended pending further evaluation.
Our patient was seen by an endocrinologist who made a diagnosis of possible hyperparathyroidism (normocalcemic hyperparathyroidism), and an ultrasound study of the thyroid and parathyroid glands was performed one month later, showing a coarsened texture of the thyroid parenchyma consistent with diffuse pathology. However, no focal mass was seen. An enlarged parathyroid gland was not detected.
In light of the dire prognosis that MND carries, and the plausibility of hyperparathyroidism causing the MND, consultation with a vascular surgeon was arranged for consideration of a parathyroidectomy. At last known follow-up our patient had continued to deteriorate.