VCOM Carolinas Research Day 2023

Clinical Case-Based Reports

DEVELOPMENT OF LEWIS-SUMNER SYNDROME (MADSAM) FOLLOWING COVID-19 INFECTION

Brandon Welborn, B.S., OMS-III, Jeff Benjamin, D.O. Edward Via College of Osteopathic Medicine, Spartanburg, SC and Bon Secours Diane Collins Neuroscience Institute

Abstract # CBR-26

Findings and Treatment

Introduction

Discussion and Conclusion

Labs

Result

Reference Range

Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), also known as asymmetrical or multifocal chronic inflammatory demyelinating polyneuropathy (CIDP) or Lewis-Sumner syndrome, is a painless asymmetric demyelinating sensorimotor mononeuropathy multiplex and is an atypical and rare variant of CIDP. 4 MADSAM is relatively rare, accounting for 5 – 10% of CIDP cases with a prevalence of 1 – 9 cases per 1,000,000 people. 13,16 No antecedent infections or vaccinations have been consistently linked to the development of CIDP, but they have preceded approximately 10% of cases, suggesting a pathophysiological link. 15 MADSAM is a dysimmune motor and sensory peripheral neuropathy that typically manifests as a chronic sensorimotor mononeuropathy multiplex with an asymmetrical, insidious onset and slow progression, affecting primarily the distal and intermediate nerve segments. 8 This disease initially involves single nerves in the upper extremities, spreads to the lower extremities, and can eventually progress to symmetrical involvement, mimicking typical CIDP. 4 Multifocal, persistent conduction blocks are also a common finding in this disease. 4 Since the onset of the COVID-19 pandemic, there have been reports of autoimmune and demyelinating diseases of the central and peripheral nervous systems related to COVID-19; however, it remains unclear whether COVID-19 is the causative agent or only a correlative. 5,10 Since 2020, all reported cases of COVID-19 neuropathy, whether virus or vaccine-related, have been Guillain-Barré syndrome, typical CIDP, or Miller Fisher syndrome-like, with one case describing the virus’s association with MADSAM. 5 This case is a unique presentation of MADSAM and strengthens the case for the emergence of COVID-19 associated CIDP like neuropathies.

References Increasing evidence suggests the emergence of autoimmune diseases following a COVID-19 infection. 10 COVID-19-associated neuromuscular diseases, including Guillain-Barré syndrome, are the second most prevalent neurological sequelae of this infection. 6 CIDP and its variants have not been consistently linked to a particular pathogen, but in this case, given the timeline of symptoms, her clinical presentation was most likely caused by an autoimmune reaction due to her prior COVID-19 infection. 15 This case is reported due to MADSAM’s rarity and to support the link between MADSAM and COVID-19 and the development of neurological disease post-infection. COVID-19 has been linked to a systemic inflammatory response and demyelinating neuropathies in the central and peripheral nervous systems; however, the pathologic basis of viral- or vaccine-related COVID-19 associated neuropathies is unclear. 12 As in this patient, MADSAM mostly presents with mixed sensory and motor symptoms (>50%); however, patients may present with primarily motor (18%) or sensory (32%) symptoms. 14 This disease classically presents as asymmetric large fiber neuropathy in a peripheral nerve distribution with asymmetric upper and lower motor and sensory dysfunction and an insidious onset that progresses over weeks to years. 7 This patient has a history of chronically elevated hemoglobin A1C, suggesting diabetic radiculopathy; however, diabetic neuropathy manifests as small fiber neuropathy which would present with impairment of pain, temperature, and autonomic functions, which are not present in this patient. Instead, this patient had loss of vibration sense, gait ataxia, decreased reflexes, increased nerve conduction velocity, and paresthesia, so we believe this to be a large fiber neuropathy. Increasing evidence suggests that patients with diabetes have a higher prevalence of CIDP and its variants. 2 Typical CIDP commonly presents with significantly elevated CSF protein due to its effects on proximal nerve segments. 3 In MADSAM patients, approximately 82% have mild to moderately elevated CSF protein. 4 As shown in this patient, MADSAM can have a normal CSF protein level due to this neuropathy predominantly affecting the intermediate and distal nerve segments. 14,18 Typical CIDP also presents with symmetrical peripheral neuropathy and areflexia, unlike in this patient. 4 Over time, MADSAM can eventually present indistinguishably from typical CIDP as the disease progresses in severity to a more symmetric pattern. 20 In MADSAM, 48% of patients have CN involvement, with 80% having unilateral palsy, whereas in typical CIDP, only 11% have CN involvement. 17 We believe this to have caused the right lower facial weakness in this patient, leading to her slurred speech. Phrenic nerve palsy has been reported in as much as 20% of acute-onset typical CIDP; however, there were no cases of PN palsy specific to the MADSAM variant found in the literature. 21 The pathophysiology behind this disease is not completely understood; however, the classical concept is that MADSAM neuropathy develops from macrophage-induced demyelination. 8 Further investigation may include an MRI and nerve biopsies. 19 These tests may show non-specific inflammation and patchy swelling in the nerve trunks and extensive onion bulb formations. 8 MADSAM can also be difficult to diagnose due to its close symptomatic relationship to other forms of atypical CIDP, typical CIDP, and multifocal motor neuropathy (MMN). MADSAM can look like MMN if it affects the upper motor nerves in an asymmetric way, but MADSAM is distinguished by the presence of sensory problems, does not have anti-GM1 antibodies, and does not cause fasciculations. 4 EMG findings in CIDP and its variants, can include full or partial conduction blocks, decreased amplitudes, slow conduction velocities, prolonged distal latencies, and delayed or absent F waves in one or more motor nerves, as presented in this patient. 9 MADSAM has also been described as having multiple conduction blocks in the intermediate nerve segment. 9 However, this patient only had one conduction block located in the peroneal nerve.

IgG/IgM anti-ganglioside-monosialic acid

Negative Negative Negative Negative

Negative Negative Negative Negative

Anti-neoplastic antibody Anti-nuclear antibody

Anti-glutamic acid decarboxylase antibodies

Cerebrospinal fluid protein

46 mg/dL 15-45 mg/dL

Creatine kinase Vitamin B12

70 U/L

21-215 U/L

550 pg/mL 0.03 nmol/L 7 mm/hr 0.5 mg/dL 2.240 mU/L

193-986 pg/mL 0.00-0.24 nmol/L 0-20 mm/hr 0.0-0.9 mg/dL 0.358-3.740 mU/L

Acetylcholine receptor panel

Sedimentation rate C-reactive protein

Thyroid stimulating hormone

Hemoglobin A1C

7.1%

4.8-5.6%

Nerve Conduction and Needle EMG Summary

Nerve Conduction Velocity: Sensory • Mild slowing in the conduction velocity of the right median sensory nerve • Prolonged latencies and mild slowing in the conduction velocities and action potentials in the bilateral sural sensory nerves were present Nerve Conduction Velocity: Sensory, Trans-Carpal • Median trans-carpal nerve markedly slowed Nerve Conduction Velocity: Motor • Right median motor nerve conduction velocity abnormal distally with increased terminal latency • Severe reduction in amplitudes of the right median nerve, right ulnar, right peroneal, and right tibial nerves with prolonged terminal latencies and very small compound muscle action potential with marked attenuation • Right ulnar nerve showed slowing across the elbow F-Wave • No response in right peroneal nerve F wave. Right tibial nerve F wave was mildly prolonged

H-Reflex • Right H-Reflex, from stimulation of the right tibial nerve, showed prolonged latency compared to the left tibial nerve Needle Electromyography (EMG) • Right flexor digitorium superficialis and tibialis anterior muscles showed significant denervation • Right extensor digitorium communis muscle showed moderate denervation • Right medial head of the gastrocnemius muscle showed mild denervation • Right flexor dorsal interosseous, extensor digitorium communis, deltoid, tibialis anterior, gastrocnemius, and vastus lateralis muscles had moderate to reduced recruitment • Right lower extremity muscles had significantly decreased amplitudes Conclusion • Findings compatible with significant distal axonal demyelinating sensorimotor polyneuropathy • No myotonia or fasciculations occurred

Clinical Case Presentation

A 48-year-old female with diabetes, asthma, and hypothyroidism was consulted by outpatient neurology following a visit to the emergency department (ED) one day prior with progressively deteriorating shortness of breath (SOB), muscle fatigue and weakness, and slurred speech. She was diagnosed with COVID-19 eight months before she went to the ED. Her current symptoms started eight weeks after she was diagnosed with COVID-19. To investigate her SOB, a chest x-ray was performed in the ED, which showed right hemi diaphragmatic paralysis. The patient was stabilized, discharged home, and referred to outpatient neurology. Physical examination findings from the patient's outpatient neurology visit are discussed below.

Pertinent Physical Exam Findings GENERAL • Alert and Oriented x 4, Mild distress HEENT • Pupils equally round and reactive to light • No ptosis, no weakness of eye muscles

Reflex Scores Triceps reflexes: 2+ left, 2+ right Bicep reflexes: 2+ left, 1+ right Brachioradialis reflexes: 1+ left, 1+ right Patellar reflexes: 2+ left, 1+ right Achilles reflexes: 1+ left, 1+ right Right grip: 1+ Left grip: 2+ Motor Exam Right arm tone: Decreased Left arm tone: Decreased Right leg tone: Decreased Left leg tone: Decreased Right foot drop: 3+/5 Bilateral arm strength: 4+/5 Able to get out of a chair with little assistance Sensory Exam Right leg vibration: Decreased, distal to proximal Left leg vibration: Decreased, distal to proximal Right leg pinprick: Decreased, distal to proximal Left leg pinprick: Decreased, distal to proximal

PULMONARY • Labored respirations • Dyspnea on exertion

Diagnosis

EXTREMITIES • Ataxic, right foot steppage gait • Moves all four extremities • Fatigable grip strength on right with repetitive use NEURO • Decreased vibration and pinprick sensation in bilateral lower extremities • Right lower facial weakness • Cranial nerve II-VI and VIII-XII intact • Negative Hoffman’s sign • Negative Lhermitte's sign • Negative for resting, intention, or action tremor

A diagnosis of MADSAM was made following extensive evaluation. This was believed to be an acquired autoimmune disease resulting from her previous COVID-19 infection in January 2022. The predominant unilateral symptoms, including right hemi-diaphragmatic paralysis and right lower facial muscle weakness with multiple asymmetric sensory and motor nerves affected, along with the nerve conduction and EMG results, make this presentation highly suspicious for the MADSAM variant of CIDP.

References

Treatment

First-line treatments, including intravenous immunoglobin (IVIG) and intravenous (IV) corticosteroids, were discussed with the patient. The patient was started on IVIG treatment for long-term maintenance. An IVIG induction dose of 2 g/kg over 5 days was started, followed by monthly maintenance doses of 0.4 g/kg with a plan to administer and adjust every 3 to 4 weeks based on the patient’s needs for a minimum of 5 years. At her 3-month follow-up visit, her reflexes, sensation, facial weakness, and right foot drop had improved (4+/5); however, the phrenic nerve palsy had not improved. After 6 months, the patient can be reevaluated to see if further treatment is needed. Both IVIG and corticosteroids (oral or IV) are first-line induction treatments for MADSAM. 3,19 Subcutaneous immunoglobin may be used instead of IVIG for maintenance. Plasma exchange has been shown to be an effective option when primary treatment with fails. 3,4,19

• Cerebellar function intact • No fasciculations noted

Imaging Chest computed tomography (CT) with contrast: Elevated right hemi-diaphragm with adjacent right basilar subsegmental atelectasis. This confirmed her paralyzed right hemi-diaphragm, which was subsequently diagnosed as phrenic nerve palsy.

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