Clinical Reasoning: A 64-year-old woman with progressive leg weakness and ophthalmoplegia

Section 1

A 64-year-old woman with type 2 diabetes (HbA1C: 6.6%) experienced pain radiating down her right leg with intermittent numbness and tingling in her feet, followed by right leg weakness and recurrent falls. Two months after onset, she required a walker to ambulate long distances. Over the next 5 months, she experienced slow and progressive right leg weakness. Her neurologic examination revealed normal cranial nerves, fasciculations in the right leg, and nonpyramidal weakness in the right L3-S1 myotomes. She had intact strength elsewhere. Reflexes were pathologically brisk (3+), except for absent right patellar and bilateral Achilles reflexes. Plantar responses were flexor. There was mild length-dependent distal sensory loss in both lower extremities.

Nerve conduction studies (NCSs) revealed attenuated motor responses throughout the right leg with relative sparing of conduction velocity. There was no motor conduction block or evidence of demyelination. Sensory responses were absent in both legs. Needle EMG revealed ongoing neurogenic denervation in multiple bilateral lumbosacral and right thoracic myotomes.

Section 2

Given the patient’s asymmetric nonpyramidal weakness, fasciculations, and sensory loss, this process localizes to lumbosacral lower motor neurons (LMNs) and peripheral nerves. A right lumbosacral radiculoplexus neuropathy with superimposed diabetic sensory polyneuropathy was considered. However, neurogenic denervation spreading to thoracic myotomes and the clinically unaffected leg argued against a unilateral radiculoplexopathy. Overall, the presentation suggested more LMN dysfunction, but pathologically brisk reflexes suggested early upper motor neuron (UMN) involvement.

Although the patient’s sensory findings and lack of weakness in other limbs was atypical, the presence of both LMN and UMN findings was suspicious for an LMN-predominant motor neuron disease (MND), such as a variant of amyotrophic lateral sclerosis (ALS), with superimposed diabetic polyneuropathy. The differential diagnosis also included motor neuronopathy and motor neuropathy, such as multifocal motor neuropathy and multifocal acquired motor axonopathy, along with diabetic sensory polyneuropathy. She had normal serum B₁₂, ceruloplasmin, protein electrophoresis, thyroid-stimulating hormone, and inflammatory panel. Creatine kinase was mildly elevated as can be seen in axonal neuropathy and MND. Nonenhanced MRI spine was normal aside from L5/S1 spondylolisthesis and moderate foraminal stenosis.

For the next 4 months, the patient remained stable. However, 11 months after her initial symptoms, she developed 5 weeks of progressive upper extremity weakness, falls, diplopia, dyspnea, and dysphagia with 25 pounds of weight loss. She noted binocular horizontal diplopia with lateral gaze, which progressed to complete paresis of horizontal gaze. She also noticed new numbness and tingling in her left leg and bilateral hands that progressed up her left arm to the elbow. There were no accompanying cognitive changes, seizures, or fevers.

The patient's examination revealed normal visual acuity and fields. Convergence and vertical gaze were intact, but horizontal eye movements were absent bilaterally. This was not overcome by the vestibulo-ocular reflex (VOR). There was LMN bilateral facial paresis. The palate elevated symmetrically, and her tongue had normal movements without fasciculations. Her speech was dysarthric. She had a brisk jaw-jerk reflex. Her motor examination revealed reduced bulk and fasciculations in the right quadriceps. Mild nonpyramidal weakness was noted in neck flexors, deltoids, and biceps bilaterally. Worsened nonpyramidal weakness was noted in the right leg. Weakness was not appreciated in the left leg. Reflexes remained pathologically brisk in the upper extremities, but were absent in the legs. Her left plantar response was flexor, but mute on the right. She had reduced vibration sense distally in the lower extremities.

Section 3

Bilateral horizontal gaze paresis not overcome by VOR, preserved convergence, and bilateral facial paresis localizes to the pons at the level of the facial colliculus, involving bilateral cranial nerve VI nuclei and the fascicles of cranial nerve VII. MRI demonstrated increased T2 fluid-attenuated inversion recovery signal in the posterior pons (figure).

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Figure Axial MRI demonstrating increased T2–fluid-attenuated inversion recovery (FLAIR) signal in the posterior pons

Axial MRI T2 FLAIR demonstrating increased signal hyperintensity in the posterior pons (as indicated by the red arrows). In the caudal pons, depicted in A and B, T2-FLAIR signal hyperintensities are visualized affecting the region of the bilateral facial colliculi and cranial nerve VI nuclei. T2-FLAIR signal hyperintensities continue into the rostral pons as indicated by the red arrows in C and D. There was no associated parenchymal, leptomeningeal, or cranial nerve enhancement with MRI T1 postgadolinium imaging. There was no evidence of restricted diffusion on diffusion-weighted imaging/apparent diffusion coefficient modalities. The remaining MRI brain and spine were both unremarkable.

Although ophthalmoplegia can rarely occur in bulbar ALS and impairment in extraocular movements occurs as a late manifestation of ALS in chronically ventilated patients, ophthalmoplegia is atypical of ALS. One consideration, given the patient’s dysphagia and weight loss, was a superimposed Wernicke causing ophthalmoplegia. However, the patient’s condition continued to worsen despite high-dose IV thiamine. Although progressive supranuclear palsy (PSP) and multisystem atrophy (MSA) can rarely co-occur with MND, the absence of vertical eye movement abnormalities, parkinsonism, autonomic dysfunction, and ataxia was not consistent with PSP or MSA. Although the examination and EMG revealed predominant LMN dysfunction, the rapidity of decline, worsened sensory symptoms, ophthalmoplegia, and pontine lesion challenged the diagnosis of ALS and broadened our differential to include inflammatory, paraneoplastic, and autoimmune etiologies affecting motor neurons and cranial nerve nuclei.

A CT chest, abdomen, and pelvis and transvaginal ultrasound did not reveal evidence of malignancy or lymphadenopathy. CSF analysis revealed protein of 503 mg/L, but otherwise cytology, cytometry, and extensive bacterial and viral studies were unremarkable. Serum anti-GQ1b, anti-GM1, and Lyme serology were negative. Repeated NCS revealed new-onset patchy, non-length-dependent loss of sensory responses in the left upper extremity. The patient was started on high-dose methylprednisolone and IV immunoglobulin (IVIg) without clinical improvement. The patient developed progressive respiratory decline, disorientation, and lethargy. An EEG did not reveal evidence of seizures and repeated MRI brain remained stable. The patient continued to decline and eventually died of respiratory failure. Her paraneoplastic antibody panel later revealed positive serum and CSF anti-Hu antibodies. The family declined autopsy.