Clinical Reasoning: A 68-Year-Old Man With Proximal Weakness and Seizures

Section 1

A 68-year-old man developed progressive weakness over 4 weeks. He had difficulty rising from a low position, climbing stairs, and raising his arms overhead, particularly toward evenings. He had no pain, sensory, or bowel or bladder symptoms, and denied ptosis, diplopia, dysphagia, or dyspnea. He had mild unintentional weight loss but no fevers. His medical history revealed eczema and active smoking (50 pack-years). There was no family history of neuromuscular disorders.

On examination, vital signs were normal; the patient was alert, oriented, attentive, and fluent with no memory disturbance. Cranial nerves revealed symmetric, reactive pupils, full extraocular movements, facial strength, and no fatigable ptosis. Muscle bulk and tone were normal without fasciculations. Neck strength was full, with variable moderate weakness in shoulder and hip girdles, slightly worse with repetition. Deep tendon reflexes were absent except biceps and patella, which were reduced but present. Sensation and coordination were unremarkable.

Section 2

The patient presents with subacute painless, proximal, symmetric weakness over 4 weeks, with possible fatigability, importantly without craniobulbar or sensory abnormalities, and reflexes are reduced or absent. Main considerations include muscle or neuromuscular junction disorders. Motor neuropathy including acute motor axonal neuropathy and multifocal motor neuropathy with conduction block, as well as motor neuron disease such as primary muscular atrophy, are unlikely without reduced tone or fasciculations. Amyotrophic lateral sclerosis is unlikely without bulbar or upper motor neuron signs. Lack of sensory symptoms makes polyradiculopathy and peripheral neuropathy unlikely, as well as spinal cord disease without sphincter dysfunction or upper motor neuron signs; notable exceptions include acute flaccid myelitis from poliovirus, nonpolio enteroviruses, and West Nile virus. This patient had no recent travel or infectious prodrome. There were no corticobulbar signs or encephalopathy to suggest other central processes.

Muscle disorders may be inflammatory or noninflammatory, congenital or acquired. Inflammatory and toxic myopathies may present with myalgias; this patient had no pain or exposures. His age and subacute presentation are atypical for most muscular dystrophies or genetic myopathies, with no relevant family history, although some genetic conditions demonstrate low penetrance or anticipation, including certain limb-girdle muscular dystrophies or Pompe disease. Myopathies may include systemic involvement, such as cardiac dysfunction, rashes (dermatomyositis), myoclonus (mitochondrial myopathies), or myoglobinuria from muscle damage, which were not present. Acquired neuromuscular junction conditions can be divided into postsynaptic disorders like myasthenia gravis (MG), associated with thymoma or presynaptic disorders such as botulism—although unlikely without pupillary involvement—and Lambert-Eaton myasthenic syndrome (LEMS), associated with smoking and small cell lung cancer (SCLC), although much less common than MG. Whereas both MG and LEMS may present with proximal weakness, the clinical phenotype is more typical for LEMS. Ocular involvement, diurnal variation, and fatigability are characteristic of MG, whereas patients with LEMS may have improvement with repetition or the day’s progression, as well as autonomic symptoms. Electrodiagnostics and serum creatine kinase levels can help distinguish the above.

On further history, the patient denied erectile dysfunction but complained of increasingly dry mouth. Repeat examination revealed postexercise facilitation of deep tendon reflexes. Serum biochemistry and creatine kinase were normal. Spinal imaging demonstrated no abnormalities. Nerve conduction studies confirmed normal sensory potentials and low compound muscle action potentials without motor conduction block, which improved with exercise (figure 1, A and B). Slow repetitive nerve stimulation (RNS) showed decrement (figure 1B), while fast RNS showed increment (figure 1C). Chest radiograph and CT showed minimal mediastinal and hilar lymphadenopathy with no suspicious pulmonary masses or thymoma. Serum voltage-gated calcium channel (VGCC) antibodies returned highly positive (387.1 pmol/L).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1 Left Ulnar Motor Studies and Repetitive Nerve Stimulation (RNS) Recording Left Abductor Digiti Minimi

(A) Motor curves stimulating at the wrist (distal), below elbow, and above elbow: low distal amplitude (4.6 mV), normal distal latency (3.2 ms), and mild slowing across the elbow without conduction block (53–39 m/s). (B) Slow repetitive nerve stimulation (RNS) (3 Hz, 10 stimulations): (a) before exercise, decremental response in amplitude (2.7–1.3 mV; 51% decrement) from stimulus 1 to 4 (blue bars); (b) following 60 seconds of maximum voluntary contraction, repair of motor amplitude (now 6.4 mV) demonstrating postexercise facilitation, but still decremental response in amplitude (6.4–5.1 mV; 21% decrement) from stimulus 1 to 4 (blue bars). (C) Fast RNS (30 Hz, 90 stimulations): incremental response in amplitude (3.0–8.2 mV; 172% increment) between stimulus 20 and 90 (blue lines). ADM = Abductor digiti minimi; ADQM = Abductor digiti quinti minimi.

Section 3

LEMS is a presynaptic neuromuscular junction disorder characterized by inhibition of P/Q-type VGCCs that mediate calcium influx, which normally respond to membrane depolarization, leading to proximal weakness and autonomic dysfunction.^1,2 Antibodies against VGCC are present in 85%–95% of cases,³ higher in paraneoplastic LEMS, which is highly associated with SCLC, found in 60% of cases, with smoking a strong risk factor.² SCLC must be considered when LEMS is diagnosed, found on initial screening in most patients. However, tumors may begin small with undetectable parenchymal lung mass and only lymphadenopathy as in this case. Immunotherapy with corticosteroids, IV immunoglobulin (IVIg), and plasma exchange (PLEX) are used; however, as with all paraneoplastic syndromes, management relies on treatment of the underlying malignancy.¹

Similar to how maximum voluntary contraction transiently increases intracellular calcium concentration, leading to postexercise facilitation and increment, symptomatic treatment targets augmentation of synaptic calcium, which increases release of acetylcholine quanta.^1,4 3,4-Diaminopyridine (DAP) blocks presynaptic potassium channels, which prolongs depolarization, leading to increased calcium influx and intracellular calcium accumulation, which improve the ability of vesicles to fuse and release acetylcholine.⁴ Acetylcholinesterase inhibitors like pyridostigmine have modest benefit and are no longer first line. Guanidine increases intracellular calcium but is not widely available due to bone marrow suppression and nephrotoxicity.⁴

The patient was treated with IVIg and 3,4-DAP with improvement in strength. Although no pulmonary mass was seen, given strong suspicion, endobronchial ultrasound was pursued, and lymph node biopsy confirmed SCLC. Staging PET and MRI brain showed limited disease confined to the lungs without brain involvement. The patient started chemotherapy with carboplatin and etoposide with planned radiotherapy. He developed neutropenia, delaying chemotherapy, followed by confusion and seizures, and was brought to the hospital and intubated for status epilepticus.

Section 4

Infectious meningoencephalitis must be considered with neutropenia and chemotherapy. Seizures are a rare side effect of 3,4-DAP from potentiation of synaptic action potentials, although reported with higher doses as CNS penetration is less than with 4-aminopyridine.⁴ New seizures in a patient with malignancy should prompt consideration for brain metastases. Limbic encephalitis would also be a strong consideration with SCLC.

EEG demonstrated frequent periodic independent epileptiform discharges in the temporal regions bilaterally (figure 2A), with recurrent electrographic seizures, which continued despite prompt discontinuation of 3,4-DAP and addition of escalating antiepileptic drugs. Broad antimicrobial coverage was started, but CSF showed normal protein, no cells, negative viral studies, and was sent for paraneoplastic antibodies. Contrast MRI showed no abnormalities to suggest metastases or encephalitis (figure 2B).

• Download figure
• Open in new tab
• Download powerpoint

Figure 2 EEG and Brain Imaging

(A) EEG recorded in longitudinal bipolar montage shows frequent independent left temporal (black arrowheads) and right temporal (white arrowheads) epileptiform abnormalities. Time base 15 mm/s, sensitivity 7 μV/mm, LF filter 0.5 Hz, HF filter 70 Hz. (B) MRI brain, T2–fluid-attenuated inversion recovery (B.a) axial and (B.b) coronal views, and T1-weighted (B.c) axial and (B.d) coronal views, showing no temporal lobe abnormalities; axial (B.e) T1-weighted post-gadolinium with (B.f) fat-saturated views, showing no abnormal enhancement.

PLEX was initiated for presumed limbic encephalitis, but seizures remained refractory without anesthetic infusions despite multiple antiepileptics. Although limbic encephalitis associated with SCLC should not be a reason to withdraw treatment, the family ultimately wished to withdraw care in respect of previous advance care directives following extensive counseling. A few days after the patient died, cell-based assay for γ-aminobutyric acid–B receptor (GABA_BR) antibodies returned highly positive from CSF.