A 58-year-old Hispanic Caucasian man with diabetes mellitus presented to the Emergency Center with a 1-year history of progressive bilateral upper extremity weakness and episodes of orthostatic lightheadedness. He initially noticed weakness in his right-hand grip that gradually progressed over the next 6 to 8 months to involve the left hand and eventually both arms, to the extent that he was unable to hold objects or elevate his arms. He also complained of a tingling and burning sensation in both hands. His family had noticed mild bilateral facial weakness, described as reduced facial expression, without dysphagia or dysarthria. He did not complain of any lower extremity weakness or sensory symptoms. There was no bowel or bladder dysfunction, and he denied any erectile dysfunction. Prior to evaluation, he had been experiencing orthostatic intolerance that worsened to the point that he became non-ambulatory. His family had also noticed cognitive decline over the last year, with frequent forgetfulness and slow thought processing. On systems review, he reported mild xerostomia and xerophthalmia without dysphagia.
A general physical examination, including cardiovascular, respiratory and abdominal systems, was normal. On initial neurological examination, he was awake, alert and oriented to person, place, time and situation. He had a Montreal Cognitive Assessment (MoCA) score of 16 out of 30, with deficits primarily in the visuospatial, executive and delayed recall domains. On cranial nerve examination, he had preserved pupillary responses, visual fields were full on confrontational testing, and he had normal fundoscopy bilaterally. His extraocular movements were preserved. He had bilateral facial weakness (facial diplegia) and decreased subjective sensation to light touch and pinprick in the left trigeminal nerve distribution. He did not have any hearing impairment and his uvula and palate elevated symmetrically. He did not have any weakness in his sternocleidomastoid, trapezius or tongue muscles. On motor testing, there was decreased tone in his upper extremities, with bilateral shoulder girdle and intrinsic hand muscle atrophy. On confrontational strength testing (based on the six-point Medical Research Council scale), he had normal neck flexion and extension strength. He had near symmetric proximal and distal weakness in the upper extremities, with strength of two to three out of five in all muscle groups tested, slightly worse on his right (Table 1). His strength was normal in his lower extremities.
On multimodal sensory examination, he had subjectively decreased sensation to light touch and pinprick in his left radial nerve, left median nerve and right axillary nerve distributions. A sensory examination of his lower extremities was normal. His triceps and patellar reflexes were diminished bilaterally, with preservation of his other myotactic stretch reflexes. His plantar responses were flexor bilaterally, and he did not demonstrate any frontal cortical release signs. Automated blood pressure and heart rate measurements performed at the bedside with postural change demonstrated severe orthostatic hypotension with sympathetic α- and β-adrenergic compromise as follows: supine blood pressure, 142/90mmHg (mean arterial pressure, MAP, 107mmHg) with heart rate 68 beats/minute; sitting blood pressure, 97/64mmHg (MAP 75mmHg) and heart rate 77 beats/minute; standing blood pressure, 65/40mmHg (MAP 48mmHg) and heart rate: 81 beats/minute.
His elevated serum hemoglobin A1C of 7.9% (normal 4.3 to 6.1%) was consistent with suboptimal diabetes control. He had a normal thyroid function screen and serum vitamin B12 levels. The results of tests for serum rapid plasma reagin, human immunodeficiency virus antibodies and a hepatitis panel were all negative. A screen for systemic vasculitides revealed an elevated anti-SSA antibody titer of 28.4EU/mL (reference range: neg <16EU/mL, equivocal 16 to 20EU/mL, positive >20EU/mL), with a normal anti-SSB titer of 0.3EU/mL (reference range: neg <16EU/mL, equivocal 16 to 20EU/mL, positive >20EU/mL). The results of the following serum or blood tests were negative, non-reactive or normal: anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, complement 3 and 4 levels and rheumatoid factor titer.
Due to his demonstrable cranial nerve deficits associated with his severe brachial diplegia and orthostatic hypotension, an infectious, infiltrative or inflammatory disorder affecting his cranial nerves and cervical nerve roots was considered. Cerebrospinal fluid analysis revealed a normal white cell count of 1/μL (normal 0 to 5), with an elevated protein level of 81mg/dL (normal 15 to 45mg/dL), and glucose of 90mg/dL (normal 50 to 80mg/dL) with serum glucose of 160mg/dL. A mildly elevated immunoglobulin (Ig) G synthesis rate of 3.8mg/day was detected (normal -9.9 to +3.3 mg/day), suggesting increased intrathecal antibody production. Magnetic resonance imaging (MRI) of his brain with and without gadolinium contrast was normal. MRI of his spine revealed mild spinal canal stenosis at C5–C6 due to a small central disc protrusion without cord compression. No changes suggestive of spinal cord or nerve root inflammation were observed.
Nerve conduction studies (NCS; Table 2) suggested a primary axonal neuropathy. Mild conduction velocity slowing or prolonged distal latency, with reduced compound motor action potential amplitudes are consistent with this inference. There was no evidence of conduction block in any of the nerves studied. The normal tibial motor and sural sensory NCS provided evidence supporting the non-length-dependent nature of the patient's axonal neuropathy. Monopolar needle electromyography revealed moderately severe chronic reinnervation changes in his radial, distal median, distal ulnar and axillary-innervated muscles bilaterally, with ongoing denervation changes in muscles innervated by his left distal median, right radial and bilateral axillary nerves only. Monopolar needle electromyography of cranial nerve VII innervated muscles revealed moderate chronic reinnervation changes bilaterally.
The electrodiagnostic data was consistent with chronic, moderately severe, axonal mononeuropathies affecting the patient's radial, median, ulnar, axillary and facial nerves; slightly worse on the left, as seen in mononeuropathy multiplex. There was also evidence of moderately severe chronic reinnervation changes affecting the L2–L4 myotomes on the left, suggestive of subclinical lumbar radiculopathies (explaining his diminished knee reflexes on examination). Secondary chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is unlikely because the clinical presentation, physical signs with preserved reflexes, were not consistent with CIDP, despite the elevated protein on cerebrospinal fluid (CSF). Moreover, the electrodiagnostic data did not meet the European Federation of Neurological Societies/Peripheral Nerve Society criteria for CIDP.
He underwent a left superficial radial nerve biopsy that demonstrated a chronic vasculitic neuropathy with ongoing Wallerian degeneration, and severe end-stage axonal loss, as shown in Figure 1. This was consistent with a diagnosis of vasculitic mononeuropathy multiplex. A salivary gland biopsy (to evaluate for xerostomia) was normal. High-dose intravenous methylprednisolone was administered for 5 days followed by oral prednisone (1mg/kg/day) with strict glycemic control. A liberal salt diet, >2L fluid intake per day, JOBST® waist high compression stockings (to provide 30 to 40mmHg pressure), and fludrocortisone were used to treat the severe orthostatic hypotension. The patient was discharged to a rehabilitation facility for upper extremity physical and occupational therapy.
Light and electron microscopy demonstrating vasculitic neuropathy. Representative photomicrographs of fixed sections obtained from the left superficial radial nerve biopsy are shown. Hematoxylin and eosin (H&E)-stained sections demonstrate severe axonal loss with almost complete depopulation of myelinated axons in a nerve fascicle (black arrow), (A) supported by the lack of neurofilament (NF) staining (black arrow) on immunohistochemistry (IHC), as shown in (B). H&E-stained sections show focal vasculitis involving small vessels with transmural lymphocytic infiltration in the epineurium (black arrow), (C), verified by CD45 (also known as leukocyte common antigen)-positive mononuclear cell infiltrates on IHC (black arrow), (D). Electron micrographs further demonstrate the severe axonal loss (~90 to 95% of large and small myelinated axons are no longer present) with residual myelinated axons (black arrows) and ongoing Wallerian degeneration (dark blue arrows) seen at lower (E) and higher magnifications (F). Original magnifications: A and B: 20×, C and D: 64×, E: 1000× and F: 5000×.
At 3-month follow up, the patient reported mild improvement in his upper extremity function, evidenced by interval objective improvement on confrontational strength testing (Table 1) and improved facial expression. There was less orthostasis, with infrequent spells of postural lightheadedness despite non-compliance with compression stockings. The repeat MoCA score was unchanged, with stable deficits in visuospatial, executive function and delayed recall, although the patient and his family had noted a subjective improvement in his cognition. He was subsequently started on azathioprine, which was titrated upwards to a total daily dose of 2mg/kg/day alongside a gradual prednisone wean.
At 1-year follow up, he demonstrated further improvement in muscle strength (Table 1) with stable cognitive deficits. He had further improvement in orthostatic hypotension, and was continued on fludrocortisone. His glycemic control had worsened with a hemoglobin A1C of 10%, and continued with a dose tapering prednisone regimen in addition to azathioprine. His hemoglobin A1C 1.5 years after hospital discharge was 9.2% on low-dose prednisone and therapeutic azathioprine. He continues to receive specialist endocrinological care for diabetes. His neurological examination at his most recent evaluation was stable, with no appreciable change on confrontational muscle strength testing.