Immunotherapy Induced Myasthenic-Like Syndrome in a Metastatic Melanoma Patient With Amyotrophic Lateral Sclerosis

Observation

A 63-year-old man with stage IV (BRAF negative) metastatic melanoma presented with progressively worsening generalized weakness after a single dose of ipilimumab and nivolumab. Prior to having received immunotherapy, he had reported 3-year gradual onset of bradykinesia, shuffling gait, muscle cramping, and foot drop. He had seen a neurologist after being diagnosed with metastatic melanoma 6 months prior and was receiving dopaminergic treatment under the surmise of paraneoplastic Parkinsonism. After immunotherapy (which was promptly discontinued thereafter), his weakness dramatically worsened, requiring multiple hospital admissions. On examination, he was noted to have upward gaze diplopia, impaired single breath count, and lower motor neuron symptoms such as lingual and upper and lower extremity fasciculations, atrophy (interosseous, deltoid, and quadriceps muscles), and tongue fibrillations. He also had upper motor neuron findings such as 3+ deep tendon reflexes with positive palmomental, bilateral crossed adductor, and Hoffman reflexes. Creatine kinase levels were normal and lumbar puncture with paraneoplastic panel was unrevealing; an extended myositis panel, myasthenic panel (acetylcholine receptor modulating, blocking, and binding antibodies), and voltage-gated calcium channel antibodies were non-diagnostic. Nonetheless, patient demonstrated significant clinical improvement after high-dose steroids, maintaining on pyridostigmine 30 mg every 8 hours and prednisone 50 mg twice a day only to worsen after steroid tapering. An electromyography (EMG) revealed evidence of a widespread neuropathic process with diffuse denervation and re-innervation (see Table 1); furthermore, a magnetic resonance imaging (MRI) displayed fatty replacement of the tongue with a bright tongue sign (Figure 1), raising suspicion for amyotrophic lateral sclerosis (ALS). He was treated with IV methylprednisolone 250 mg/day and IV immunoglobulin at 1 gm/kg over 2 days followed by 5 cycles of plasmapheresis 1 week later due to high suspicion for superimposed myasthenic-like syndrome, but unfortunately died from acute hypoxic respiratory failure.

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Table 1.

Results of electromyography.

Name	Insertional activity	Fibrillations	Positive Sharp Waves	Polyphasia	Fasciculations	Recruitment
L. Tibialis Ant	Increased	2+	1+	Increased	++	Decreased
L. Gastroc. Med	Normal	2+	1+	Increased	++	Decreased
L. Biceps Brach	Normal	2+	1+	Increased	++	Decreased
L. Deltoid	Increased	3+	1+	Increased	++	Decreased

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Figure 1.

Bright tongue sign.

Discussion

Prior literature has reported exacerbations of underlying multiple sclerosis ² and myasthenia gravis ³ in the context of ICI administration. However, this represents the first case of its kind where a patient with suspected underlying ALS developed worsening neurological deficits post-ICI administration.

A key point in this case was the fact that initial diagnosis of ALS was confounded by generalized systemic weakness in the context of known melanoma, as well as the surmised diagnosis of paraneoplastic Parkinsonism. However, after ICI administration, while the patient also suffered from a concomitant myasthenic-like syndrome that was responsive to steroids and pyridostigmine, clinical findings suggestive of ALS also emerged more dramatically (Figure 2). Whether this was attributable to the natural temporal progression of ALS or an immunomodulatory effect remains unclear.

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Figure 2.

Timeline of events (milestones are presented without regard to timescale). ALA indicates amyotrophic lateral sclerosis; ICI, Immune checkpoint inhibitor.

While use of ICIs has been cautioned against in presence of known autoimmune diseases due to potential precipitation of flare-ups,^4,5 such caveats have not heretofore been expressed for ALS, given its neuroinflammatory status has been contentious in the literature thus far. ⁶ This case report suggests caution is prudent in suspected ALS cases, with careful evaluation of ICI risks before initiation.

The case report suggests pre-existing neurological deficits, including ALS, could be risk factors for NIRS, and more specific neurological screening may serve to risk-stratify patients prior to treatment with ICIs. Further research regarding the safety of ICI use in patients with underlying neurological deficits may guide future therapeutic decision-making.