A Young Woman's Journey with Unexplained Back Pain, Leg Stiffness, and Falls

Table of Contents

• Background: The Patient's Story
• Symptom Timeline and Medical History
• Diagnostic Testing and Imaging Results
• Physical Examination Findings
• Differential Diagnosis: What Could This Be?
• Reaching the Correct Diagnosis
• Diagnostic Confirmation Process
• Treatment and Management Approach
• What This Means for Patients
• Limitations and Considerations
• Patient Recommendations
• Source Information

Background: The Patient's Story

A 30-year-old woman presented to Massachusetts General Hospital's neurology clinic with a three-year history of back pain and leg stiffness that severely impacted her quality of life. Her case demonstrates how complex neurological conditions can be challenging to diagnose, often requiring multiple specialist evaluations over an extended period.

This previously healthy woman began experiencing symptoms at age 27 that would eventually lead to a rare autoimmune diagnosis. Her journey highlights the importance of persistent medical investigation when symptoms don't follow typical patterns or respond to conventional treatments.

Symptom Timeline and Medical History

The patient's symptoms began abruptly three years before her current evaluation when she developed stiffness in her back and upper legs while attempting to rise from a seated position. She simultaneously experienced low back pain that worsened with bending her knees or climbing stairs.

Over the next several months, her symptoms fluctuated significantly. At times, she could walk normally and even engage in running exercise, while at other times, her knees felt "locked up" and she was unable to walk. Two months after symptom onset, she experienced an unusual fall where she couldn't prevent herself from falling due to leg tension, resulting in a broken right arm.

Her medical history included several autoimmune conditions:

• Vitiligo (a condition causing loss of skin color)
• Eczema (inflammatory skin condition)
• Alopecia areata (autoimmune hair loss)
• Graves' disease (autoimmune thyroid disorder) in remission
• Immune thrombocytopenia (low platelet count) diagnosed 7 years earlier

Two and a half years before presentation, a rheumatology evaluation found guarded passive flexion of the left knee but otherwise normal examination and unremarkable hip and knee radiographs. One and a half years before presentation, she was diagnosed with patellofemoral pain syndrome (knee pain around the kneecap) after sports medicine evaluation, which resolved with physical therapy, but leg stiffness persisted.

Three months before presentation, she noticed increased leg stiffness (worse in the right leg), unsteadiness, and worry about falling. She hit her leg on a coffee table, both legs stiffened, and she fell, striking her face on the floor without loss of consciousness.

Diagnostic Testing and Imaging Results

The patient underwent multiple imaging studies during her diagnostic journey. Magnetic resonance imaging (MRI) of the lumbar spine performed without contrast showed:

• Normal paraspinal soft tissues
• Exaggeration of normal lumbar lordosis (curve)
• Preserved vertebral height
• Loss of normal signal intensity at L4-L5 intervertebral disk space on T2-weighted images, consistent with mild degeneration
• Severe motion artifact limited evaluation of spinal cord and nerve roots
• No evidence of high-grade spinal canal or foraminal stenosis (narrowing)

Subsequent MRI of the thoracic and lumbar spine with contrast showed:

• No specific cord abnormality
• Mild degenerative changes in thoracolumbar spine
• No moderate or severe narrowing of spinal canal or neural foramina
• No abnormal enhancement
• Possible atrophy of posterior paraspinal musculature in lower lumbar spine
• Exaggeration of normal lumbar lordosis

Laboratory testing revealed:

• Normal electrolytes and kidney function
• Creatine kinase level: 33 U/L (normal range: 26-192)
• C-reactive protein level: 1 mg/L (normal range: 0-10)
• Erythrocyte sedimentation rate: 2 mm/hour (normal range: 0-20)

Physical Examination Findings

On examination in the neurology clinic, the patient appeared anxious but was in no acute distress. Her vital signs showed:

• Temperature: 36.6°C
• Blood pressure: 141/91 mm Hg
• Pulse: 100 beats per minute
• Respiratory rate: 16 breaths per minute
• Oxygen saturation: 98% on room air
• Body mass index: 21.7

Neurological examination revealed:

• Normal strength in arms and legs
• Mildly increased tone in the legs
• No fasciculations (muscle twitches)
• Deep-tendon reflexes: 2+ in arms, 3+ in legs
• Nonsustained clonus in ankles (rhythmic muscle contractions)
• Exaggerated startle response
• Normal sensation
• Reduced knee flexion and wide-based gait when walking

Differential Diagnosis: What Could This Be?

The medical team considered multiple neurological conditions that could cause episodic muscle stiffness. They systematically evaluated possibilities from both peripheral and central nervous system disorders.

Peripheral Nervous System Disorders:

• Myotonic disorders: Conditions like myotonia congenita and paramyotonia congenita cause muscle stiffness due to delayed relaxation after contraction. However, these typically begin in childhood and show specific patterns not seen in this patient.
• Peripheral nerve hyperexcitability syndromes: Conditions like cramp-fasciculation syndrome cause muscle stiffness but are accompanied by visible muscle twitching (fasciculations or myokymia), which this patient didn't have.

Central Nervous System Disorders:

• Splasticity: Increased muscle tone from upper motor neuron dysfunction, but severity is usually consistent across examinations, unlike this patient's fluctuating symptoms.
• Rigidity: Consistent increased muscle tone seen in Parkinson's disease, but the patient lacked other parkinsonian features like tremor or bradykinesia.
• Dystonia: Sustained muscle contractions causing abnormal postures, but symptoms are usually stereotyped and relieved by sensory tricks, which didn't fit this case.
• Paroxysmal dyskinesia: Episodic involuntary movements, but typically begin in childhood with very brief episodes (under 1 minute) occurring multiple times daily.
• Hyperekplexia: Exaggerated startle response followed by stiffness, but genetic forms begin in infancy.

Reaching the Correct Diagnosis

The medical team determined that stiff-person syndrome best explained the patient's symptoms. This rare autoimmune neurological disorder is characterized by:

• Muscle stiffness and painful spasms
• Gait dysfunction with falls
• Exaggerated startle response
• Impaired GABA-mediated inhibition of motor neurons

Several features specifically pointed to this diagnosis:

• Symptoms began in paraspinal and abdominal muscles, progressing to proximal legs
• Stiffness triggered by sudden movement, physical touch, emotional upset, and startle response
• Exaggerated startle response observed on examination
• History of multiple autoimmune conditions (present in >50% of stiff-person syndrome patients)
• Dramatic improvement with benzodiazepine treatment (lorazepam temporarily normalized her gait)
• Increased deep-tendon reflexes (present in 70% of cases)
• Lumbar hyperlordosis (abnormal spinal curvature) noted on imaging

The median age of onset for stiff-person syndrome is 35-40 years, and this patient's symptoms began at age 27. Her extensive autoimmune history (vitiligo, eczema, alopecia areata, Graves' disease, and immune thrombocytopenia) significantly increased suspicion for an autoimmune neurological disorder.

Diagnostic Confirmation Process

To confirm the diagnosis, the medical team tested for glutamic acid decarboxylase 65 (GAD65) autoantibodies, which are detected in 60-90% of patients with classic stiff-person syndrome. The patient's serum was tested using a radioimmunoassay.

The results showed a GAD65 autoantibody level of 169 nmol per liter. The testing laboratory uses 20 nmol per liter as the cutoff value to indicate neurological autoimmune disease. The patient's value of 169 nmol/L falls within the typical range for patients with GAD65 autoantibody-associated stiff-person syndrome when tested in the same laboratory.

It's important to note that GAD65 autoantibodies can also be found in patients with type 1 diabetes mellitus, autoimmune thyroiditis, and pernicious anemia, but typically at lower titers than those seen in neurological autoimmune diseases. The medical team ruled out these conditions through additional testing, including normal glycated hemoglobin levels (ruling out type 1 diabetes).

Treatment and Management Approach

The medical team discussed that if GAD65 autoantibody testing had been negative, they would have considered testing for other autoantibodies associated with stiff-person syndrome, including:

• Glycine receptor autoantibodies
• Amphiphysin autoantibodies
• Dipeptidyl-peptidase-like protein 6 autoantibodies

Electromyography could also have been performed to assess for continuous motor-unit activity in paraspinal muscles or simultaneous contraction of agonist and antagonist muscle pairs, which are characteristic of stiff-person syndrome.

An important aspect of management involved ruling out paraneoplastic syndromes (cancer-related neurological disorders). Although relatively uncommon in classic stiff-person syndrome presentations, elevated GAD65 autoantibody levels have been associated with:

• Breast cancer
• Lymphoma
• Thymoma

The patient would likely require appropriate cancer screening, potentially including positron-emission tomography and computed tomography scans, to rule out these associated malignancies.

What This Means for Patients

This case illustrates several important points for patients experiencing unexplained neurological symptoms:

First, the diagnosis of stiff-person syndrome is often delayed because symptoms can be mistaken for more common conditions. The average time to diagnosis is typically several years, as was the case with this patient who experienced symptoms for three years before receiving the correct diagnosis.

Second, the fluctuating nature of symptoms and response to benzodiazepines can sometimes lead to misattribution to psychiatric causes. Many patients with stiff-person syndrome have coexisting anxiety, depression, or agoraphobia, and the relief provided by benzodiazepines may mistakenly suggest the symptoms are primarily psychological rather than neurological.

Third, stiff-person syndrome is frequently confused with functional neurological disorder. However, key distinguishing features include:

• Exaggerated startle response
• Unexplained and injurious falls
• Associated systemic autoimmunity
• Hyperreflexia (overactive reflexes)

All of these features were present in this patient, helping to guide the correct diagnosis.

Limitations and Considerations

While this case provides valuable insights, several limitations should be considered. The diagnosis relied heavily on the GAD65 autoantibody test result, and different testing methods (radioimmunoassay vs. ELISA vs. tissue-based indirect immunofluorescence assay) can produce significantly different values.

The patient's dramatic response to benzodiazepines was an important diagnostic clue, but benzodiazepine responsiveness can also occur in other conditions, including some functional neurological disorders. The combination of multiple supportive features was necessary for confident diagnosis.

Additionally, while the patient had extensive autoimmune history, not all patients with stiff-person syndrome have such clear autoimmune backgrounds. The absence of other autoimmune conditions doesn't rule out the diagnosis.

Patient Recommendations

For patients experiencing similar symptoms, this case suggests several important recommendations:

1. Persist in seeking answers when symptoms don't improve with initial treatments or don't fit typical patterns
2. Keep detailed records of symptom patterns, triggers, and responses to medications
3. Consider autoimmune causes for neurological symptoms, especially if you have a personal or family history of autoimmune disorders
4. Request specialist evaluation with neurologists experienced in movement disorders or autoimmune neurology
5. Discuss appropriate testing for autoimmune neurological conditions if symptoms suggest stiff-person syndrome

For patients diagnosed with stiff-person syndrome, treatment typically involves:

• Benzodiazepines (diazepam is most commonly used)
• Other GABA-enhancing medications
• Immunotherapy in some cases ( intravenous immunoglobulin, steroids, or other immunomodulators)
• Physical therapy focused on safety and fall prevention

Source Information

Original Article Title: Case 14-2024: A 30-Year-Old Woman with Back Pain, Leg Stiffness, and Falls

Authors: Christopher T. Doughty, M.D., Pamela W. Schaefer, M.D., Kate Brizzi, M.D., and Jenny J. Linnoila, M.D., Ph.D.

Publication: The New England Journal of Medicine, May 9, 2024;390:1712-9

DOI: 10.1056/NEJMcpc2312733

This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine. It maintains all original medical information while making it accessible for patients and caregivers.