Patient Case Study: A Rare Neurological Disease Diagnostic Journey

Rare diseases are not rare. About 25 to 30 million Americans live with rare diseases, which equates to 1 in 10 Americans. Patients with rare diseases encounter significant obstacles in achieving a timely and accurate diagnosis.

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Health care professionals must be aware of the existence and clinical features of these conditions to avoid misdiagnosis or delayed treatment. Multidisciplinary collaboration and education are vital in improving disease awareness, promoting early diagnosis, and enhancing the overall management of rare diseases.

SP is a 64-year-old male who initially presented to his primary care provider (PCP) with lower back pain that progressed to numbness in his lower extremities the following day. He was referred to physical therapy and prescribed prednisone for possible sciatica.

SP experienced an improvement in numbness for a few weeks. The following month, he reported his pain was gone but still experienced some leg discomfort. He was also diagnosed with COVID-19. Post COVID, he experienced significant weight loss.

Two months after the initial visit, he followed up again with his PCP due to the significant weight loss. SP was sent to the emergency department for CT imaging. In 3 months, and after multiple ED visits, SP's condition deteriorated to the point where he required assistance to walk just a few steps, developed a burning sensation around his lower abdomen, and lost sensation from the knee down.

SP had unremarkable findings from the abdominal CT imaging and upper endoscopy. Upon worsening abdominal pain, described by SP as “burning, crampy and knife-like,” further diagnostic testing was ordered. An MRI conducted revealed longitudinally extensive transverse myelitis (LETM).

Medications

• Prednisone 10 mg daily
• Gabapentin 400 mg TID
• Baclofen 20 mg QID
• Acetaminophen 650 mg daily prn
• Famotidine 40 mg daily
• Vitamin D3 1000 units daily
• Bisacodyl 10 mg suppository daily prn
• Docusate sodium 100 mg daily
• Magnesium hydroxide susp 30 mL daily prn
• Senna 8.6 mg daily prn

Labs

• AST – 23 U/L
• ALT – 29 U/L
• Neutrophils – 67.1%
• Hep B – Negative
• Hep C – Negative
• QuantiFERON TB – Negative
• Aquaporin 4 AB – Positive

Sensory exam

• Right facial weakness
• Burning sensation around lower abdomen
• Right and left leg light tough and vibration decrease from knee down.

Discussion

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease that primarily affects the central nervous system (CNS).^1,2 It is characterized by severe attacks of optic neuritis and/or myelitis, leading to possible visual loss, paralysis, cognitive impairment, sensory deficits, bladder dysfunction, and even mortality.²

Aquaporin-4 (AQP4)-Ab (+) NMO is a subtype within NMOSD, with AQP4 antibodies targeting the AQP4 water channel protein expressed on astrocytes in the CNS leading to demyelination and axonal loss.¹

The prevalence of NMO is estimated to be 0.16 cases per 100,000 individuals.¹ The low frequency of the disease makes it unfamiliar to many health care professionals, leading to a lack of awareness about its clinical presentation and diagnostic criteria.

NMO shares overlapping symptoms with other conditions, such as multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM).² Optic neuritis and myelitis, hallmark features of NMO, can also occur in these disorders, causing diagnostic confusion and potential misdiagnosis and delays in appropriate treatment.

In the case of patient SP, the rarity of NMO, and the overlapping symptoms initially posed diagnostic challenges. However, the identification of LETM on the MRI and the presence of AQP4 antibodies in the patient's serum supported the diagnosis of AQP4-IgG (+) NMO.

NMO predominantly affects women, with a male-to-female ratio of 1:10, and typically presents between 30 and 50 years of age.¹ Without appropriate treatment, the disease can lead to significant disability and reduced quality of life with relapses resulting in only partial recovery.

Patients experience incomplete to no recovery in 66% of optic neuritis attacks, and greater than 80% of transverse myelitis attacks.2 If left untreated, within 5 years of their first attack, roughly 50% of patients will be wheelchair bound and blind, and one-third will have died.³ With advances in treatment, the quality of life, and life expectancy of NMO patients has significantly improved.

The management of NMO involves acute attack treatment, relapse prevention, and long-term disease control. SP was started on high-dose IV corticosteroids, methylprednisolone 1 g for 5 days to control acute exacerbations. Additionally, plasmapheresis was performed to rapidly remove pathogenic AQP4 antibodies.

For relapse prevention and long-term disease control, immunosuppressive therapies are crucial. SP was started on satralizumab (Enspryng), a subcutaneous injection to stabilize the disease state. Other immunosuppressants, such as rituximab, an anti-CD20 monoclonal antibody, azathioprine, mycophenolate mofetil, and methotrexate may also be considered based on the patient's response and tolerance to treatment.

Satralizumab is a newer therapeutic option approved for the treatment of AQP4-IgG (+) NMO. It acts as an immunosuppressive therapy by targeting the interleukin-6 (IL-6) receptor.

Satralizumab binds to the IL-6 receptor, inhibiting IL-6 signaling, modulating the immune response, reducing the production of AQP4 autoantibodies, and reducing the inflammatory response in the CNS. Satralizumab binding to the antigen is pH dependent, allowing it to be released for repeated antigen binding, increasing its elimination half-life in a process called antigen-recycling.⁴ Its mechanism of action helps to control disease activity and prevent relapses, decreasing relapse rates by 74% in AQP4-IgG (+) patients compared to placebo demonstrated in the SAkuraStar trial.⁴

Satralizumab is administered as a subcutaneous injection of 120 mg at weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks.⁵ Patients should be counseled regarding the importance of adhering to the prescribed dosing schedule.

It is important to note that satralizumab, like other immunosuppressive therapies, carries potential risks and adverse effects (AEs). Patients receiving satralizumab should be counseled on and closely monitored for any AEs, such as infections, reactivation of hepatitis B and tuberculosis, injection-related reactions and irritations, liver function abnormalities, neutrophil counts, and hypersensitivity reactions.⁴

This case study underscores the difficulties faced in correctly diagnosing rare diseases such as NMO. The average time for an accurate diagnosis for a rare disease is between 4 to 5 years.

The rarity of the condition, overlapping symptoms, limited disease awareness, and reliance on specific diagnostic markers contribute to the diagnostic challenge. Early recognition and accurate diagnosis are imperative for appropriate management of NMO to prevent lasting irreversible neurological damage. Increased awareness, collaboration among health care professionals and access to specialized testing are crucial for improving the accuracy and timeliness of rare disease diagnoses such as NMO.

Patients with NMO face a significant economic burden due to increased health care utilization, long-term treatments, neuroimaging, and routine provider visits. The authors of a retrospective study reported that the overall health care expenditure attributable to NMOSD was approximately $52,000 per patient.⁵

Relapses contributed an additional $10,070 per patient, with hospital and inpatient care being more expensive than ambulatory and outpatient care.⁷ Studies have estimated that approximately 60% of costs incurred by patients with NMOSD is due to the high cost of prescriptions for long-term immunosuppression.

Health-system integrated specialty pharmacies are uniquely positioned to meet this need by offering a dedicated team for medication assistance programs. In addition, easy access to the patients’ medical records can reduce the prior authorization turnaround times, leading to patients’ initiating therapy sooner than an external specialty pharmacy.

About the Authors

Justin Bivona, PharmD, is a specialty clinical pharmacist working in multiple sclerosis and rare diseases at the Outpatient Pharmacy Services (OPS).

Bisni Narayanan, PharmD, MS, is the supervisor for operations at OPS. OPS is a specialty pharmacy integrated within the Yale New Health System.

References

1. Jarius S, Paul F, Weinshenker BG, Levy M, Kim HJ, Wildemann B. Neuromyelitis optica. Nat Rev Dis Primers. 2020;6(1):85. Published 2020 Oct 22.
2. Chan KH, Lee CY. Treatment of Neuromyelitis Optica Spectrum Disorders. Int J Mol Sci. 2021;22(16):8638. Published 2021 Aug 11.
3. Huda S, Whittam D, Bhojak M, Chamberlain J, Noonan C, Jacob A. Neuromyelitis optica spectrum disorders. Clin Med (Lond). 2019;19(2):169-176.
4. Enspryng [package insert] Genentech; 2022
5. Royston M, Kielhorn A, Weycker D, et al. Neuromyelitis Optica Spectrum Disorder: Clinical Burden and Cost of Relapses and Disease-Related Care in US Clinical Practice. Neurol Ther. 2021;10(2):767-783.