In a patient with SOD1‑related ALS receiving Qalsody (tofersen) and riluzole who is experiencing worsening breathing and progressive speech difficulties, what is the appropriate management?

Management of Progressive Respiratory and Bulbar Symptoms in SOD1-ALS on Tofersen and Riluzole

Continue tofersen and riluzole while immediately initiating respiratory support with non-invasive ventilation (NIV) and implementing aggressive secretion management strategies, as worsening breathing and speech indicate bulbar involvement that requires urgent multidisciplinary intervention to preserve quality of life and prolong survival.

Immediate Respiratory Assessment and Intervention

Your patient's breathing problems require urgent evaluation and intervention. Perform pulmonary function testing immediately including forced vital capacity (FVC), maximal inspiratory/expiratory pressures (MIP/MEP), and sniff nasal inspiratory pressure (SNIP) 1. Given the progression of symptoms, these tests should be done now rather than waiting for the routine 6-month interval.

NIV Initiation Criteria

• Start NIV if FVC <65% predicted, MIP <60 cm H2O, or evidence of nocturnal hypoventilation 1
• Polysomnography is not mandatory for NIV initiation in adults—PFT criteria alone are adequate 1
• Individualize NIV settings (mode, inspiratory time, pressures) with a backup respiratory rate for better patient-ventilator synchrony 1

Critical Bulbar Consideration

The progressive speech difficulties signal bulbar involvement, which creates a therapeutic urgency. Patients with bulbar impairment may not tolerate NIV or achieve adequate ventilation 1. This means:

• Assess bulbar function immediately (swallowing evaluation, speech clarity)
• If bulbar function remains relatively preserved, mouthpiece ventilation (MPV) can supplement nocturnal NIV for daytime support 1
• If bulbar dysfunction is severe with frequent aspiration, insufficient cough, or NIV intolerance, discuss invasive mechanical ventilation via tracheostomy early 1

Continue Disease-Modifying Therapy

Do not discontinue tofersen. The FDA label shows that while the primary ALSFRS-R endpoint was not statistically significant in the initial 28-week trial, the open-label extension demonstrated meaningful benefits with early initiation 2. More importantly:

• Long-term data (up to 3.5 years) show early tofersen initiation resulted in less functional decline (ALSFRS-R: -9.9 vs -13.5 points at 148 weeks) and better respiratory preservation (SVC: -13.8% vs -18.1%) compared to delayed start 3
• Real-world multicenter data confirm that 9 of 17 patients substantially stabilized or improved with tofersen over 48-108 weeks 4
• Neurofilament light chain reductions occur consistently and predict treatment response 2, 5

Continue riluzole concurrently—62% of patients in the pivotal tofersen trial were on riluzole, and there are no contraindications to combination therapy 2.

Speech and Bulbar Management

The progressive speech difficulties require immediate speech-language pathology referral for:

Communication Strategies

• Augmentative and alternative communication (AAC) devices should be introduced now, before speech becomes unintelligible 6
• Early AAC introduction allows the patient to learn the system while still able to speak, improving long-term communication quality of life
• Voice banking should be pursued immediately if not already done

Sialorrhea Management (if present)

Progressive bulbar dysfunction often causes troublesome drooling:

1. First-line: Oral anticholinergic medication (glycopyrrolate, atropine drops) 1
2. Second-line: Botulinum toxin injections to salivary glands if anticholinergics fail or cause intolerable side effects 1

Secretion Clearance

With bulbar involvement and respiratory decline:

• Implement lung volume recruitment (LVR) with breath stacking using a handheld resuscitation bag or mouthpiece 1
• Assess peak cough flow (PCF)—if <270 L/min, mechanical insufflation-exsufflation (cough assist device) is indicated
• Optimize airway clearance to prevent pneumonia, which is a leading cause of mortality in ALS

Monitoring Strategy Going Forward

Increase Assessment Frequency

• PFTs every 3 months (not 6 months) given active progression 1
• ALSFRS-R monthly to track functional decline rate
• Bulbar function assessment at each visit (swallowing, speech, secretion management)

Biomarker Monitoring

• Plasma neurofilament light chain levels every 3-6 months to confirm tofersen biochemical response 2, 5
• CSF SOD1 protein if accessible (though plasma NfL is adequate for monitoring)

Goals of Care Discussion

Initiate advance care planning conversations now, not later. With bulbar involvement and respiratory decline, discuss:

• Preferences regarding invasive mechanical ventilation via tracheostomy
• The reality that tracheostomy may require institutionalization and creates significant caregiver burden 1
• Hospice and palliative care options if the patient declines invasive ventilation

This discussion should happen while the patient can still communicate preferences clearly, before speech becomes unintelligible.

Common Pitfalls to Avoid

1. Delaying NIV initiation: Respiratory failure can occur rapidly in ALS. Don't wait for severe dyspnea—objective PFT criteria should trigger NIV 1

2. Assuming tofersen failure: The patient's progression doesn't mean tofersen isn't working. Natural history data suggest they might be declining faster without it 3. Continue therapy unless there are safety concerns

3. Overlooking nutrition: Progressive bulbar dysfunction increases aspiration risk. Gastrostomy tube placement should be discussed before FVC drops below 50% predicted, as the procedure becomes higher risk with advanced respiratory compromise

4. Missing CSF pleocytosis from tofersen: While continuing tofersen, remain vigilant for neurological adverse events (occurred in 7% of recipients) 7. Most are reversible, but some patients developed acute motor radiculitis requiring steroids 4

5. Inadequate secretion management: Thick secretions with inadequate cough are a medical emergency in ALS. Aggressive management prevents pneumonia and respiratory crises 1