A Decade of Debilitating Fatigue in a 33-Year-Old Woman with Complex Comorbidities

Case at a Glance

A 33-year-old female presents with a more than 10-year history of severe, debilitating chronic fatigue, hypersomnolence, and post-exertional malaise that significantly impairs her occupational and daily functioning. Despite extensive consultations with multiple specialists and numerous lab investigations, a definitive diagnosis remains elusive. Her clinical picture is complicated by a history of polycystic ovary syndrome (PCOS) and several neuropsychiatric conditions, including autism spectrum disorder and ADHD.

Patient's Story

The patient is a 33-year-old female who has experienced life-altering fatigue for over a decade. The onset was gradual, and the severity has rendered her unable to maintain full-time employment or participate in normal life activities. She describes a constant state of exhaustion, punctuated by 'sleep attacks'—sudden, overwhelming urges to sleep during the day. She frequently takes unprompted naps in the daytime and evening but reports no subsequent improvement in her energy levels. A key feature of her condition is profound post-exertional malaise (PEM), where even minor physical activity results in extreme fatigue, brain fog, and physical discomfort that can last for several days. She also notes that emotional stress can trigger similar episodes of fatigue and napping.

Initial Assessment

The patient has a complex medical history. Diagnoses include Autism Spectrum Disorder (Level 1), ADHD (inattentive type), Post-Traumatic Stress Disorder (PTSD), Major Depressive Disorder, Generalized Anxiety Disorder, Obsessive-Compulsive Disorder (OCD), Polycystic Ovary Syndrome (PCOS), and Delayed Sleep Phase Disorder. She is a non-smoker with rare alcohol use and no history of illicit drug use.

Her current medication regimen includes duloxetine 50mg, drospirenone/estetrol (Nextstellis), quetiapine 25mg, and armodafinil, which is being titrated between 112.5mg and 150mg. Previous unsuccessful medication trials include escitalopram, various stimulants (Adderall, Focalin), and atomoxetine. She supplements with low-dose melatonin, L-methylfolate, vitamin D3, and fish oil.

She has been evaluated by an immunologist/allergist, a sleep medicine specialist, a gynecologist, and an endocrinologist.

The Diagnostic Journey

The diagnostic workup has been extensive but largely unrevealing. Multiple tests, including a complete metabolic panel, comprehensive hormone panels, immune markers, a complete blood count (CBC), and C-Reactive Protein (CRP), have shown no significant abnormalities. A previously elevated DHEA level, likely related to her PCOS, normalized after she began treatment with the combined oral contraceptive Nextstellis.

A significant barrier in her evaluation has been the inability to undergo a formal in-lab polysomnography (sleep study) due to insurance constraints, leaving primary sleep disorders like narcolepsy and sleep apnea formally unevaluated, although they remain on the differential.

The constellation of symptoms, particularly the prominent post-exertional malaise, strongly suggests a diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, other potential contributors or alternative diagnoses were considered:

1. Undiagnosed Sleep Apnea: Given the reports of hypersomnolence and unrefreshing sleep, obstructive sleep apnea (OSA) remains a possibility. Mild OSA can cause severe daytime symptoms, and a home sleep apnea test was suggested as a more accessible alternative to an in-lab study.
2. Nutritional Deficiencies: Although a CBC was normal, specific deficiencies not captured by this test, such as low ferritin (iron deficiency without anemia), vitamin B12, or vitamin D, could be contributing to her fatigue.
3. Subclinical Autoimmune/Rheumatologic Disease: While initial inflammatory markers were normal, some autoimmune conditions can present primarily with fatigue before other systemic signs emerge.
4. Neurological Conditions: A non-convulsive seizure disorder (e.g., focal epilepsy) can present with episodes of altered awareness, fatigue, and cognitive dysfunction, warranting a neurological evaluation and potentially an EEG.
5. Suboptimal Management of Comorbidities: It was questioned whether her current stimulant, armodafinil, was providing adequate treatment for her ADHD and/or hypersomnolence, or if an alternative agent or dosage might be more effective.

Final Diagnosis

The final diagnosis is not yet established. The leading working diagnosis is Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), based on the long-standing history of debilitating fatigue, cognitive dysfunction, and hallmark post-exertional malaise.

Other conditions requiring exclusion include:

• Undiagnosed primary sleep disorder (e.g., Obstructive Sleep Apnea, Narcolepsy)
• Fatigue secondary to inadequately managed neuropsychiatric conditions (ADHD, Depression)
• Underlying occult rheumatologic or neurological disorder.

Treatment Plan

A multidisciplinary approach was recommended to address the patient's symptoms and continue the diagnostic process:

1. Further Investigation:

   • Sleep Evaluation: Prioritize obtaining a sleep study. A home sleep apnea test is a practical first step to rule out OSA.
   • Neurology Consultation: Refer to a neurologist to assess for underlying neurological causes, including consideration of an EEG.
   • Nutritional Labs: Order specific tests for ferritin, vitamin B12, and 25-hydroxy vitamin D.

2. Symptom Management (Pacing): Introduce the concept of activity management, or 'pacing,' to help the patient manage her energy envelope and avoid triggering post-exertional malaise. This is a core management strategy for ME/CFS.

3. Medication Optimization:

   • Collaborate with her psychiatrist to systematically review the efficacy of her psychotropic medications, particularly armodafinil. An alternative stimulant or dose adjustment may be warranted.
   • Continue established treatments for PCOS, depression, and anxiety, while remaining vigilant for medication side effects that could exacerbate fatigue.

Outcome and Follow-up

The patient remains significantly debilitated by her symptoms. The immediate plan is to pursue the recommended investigations, particularly the sleep study and neurology consult, to clarify the diagnosis. In parallel, she will be educated on pacing strategies to improve her functional baseline and quality of life. Long-term management will require ongoing, coordinated care between her primary physician, psychiatrist, and other specialists to address her complex web of symptoms and comorbidities.