What are the neurological manifestations of Whipple's disease?

Neurological Manifestations of Whipple's Disease

The neurological manifestations of Whipple's disease are diverse and may include cognitive impairment, abnormal movements (particularly oculomasticatory myorhythmia), supranuclear gaze palsy, hypothalamic dysfunction, seizures, and ataxia. These manifestations can occur in patients with systemic disease or as isolated central nervous system (CNS) involvement, and represent a significant cause of morbidity and mortality if not properly diagnosed and treated.

Clinical Presentation of Neurological Involvement

Prevalence and Timing

• CNS involvement occurs in approximately 10-20% of Whipple's disease cases 1
• Neurological symptoms can present in three distinct scenarios:
  • As part of classic systemic Whipple's disease
  • As isolated CNS infection without systemic manifestations
  • As a neurological relapse in previously treated Whipple's disease 1

Common Neurological Manifestations

1. Cognitive Dysfunction (61% of cases) 1

   • Memory loss
   • Attention deficits
   • Frontal lobe syndrome
   • Progressive dementia

2. Movement Disorders (39% of cases) 1

   • Oculomasticatory myorhythmia (pathognomonic)
   • Myoclonus
   • Choreiform movements
   • Upper motor neuron symptoms (44%)
   • Extrapyramidal symptoms (33%)

3. Ocular Abnormalities

   • Supranuclear gaze palsy
   • Ophthalmoplegia (17%) 1
   • Uveitis, retinitis, optic neuritis 2

4. Hypothalamic Dysfunction

   • Sleep disorders (hypersomnia in 17% of cases) 1
   • Polydipsia
   • Hyperphagia 3

5. Other Manifestations

   • Seizures (can lead to confusion or coma in 17% of cases) 1
   • Cerebellar ataxia (11%) 1
   • Psychiatric manifestations (delirium in 17% of cases) 1
   • Meningitis

Diagnostic Approach

Neuroimaging Findings

• Brain MRI may reveal:
  • Focal lesions (35% of cases), often tumor-like 1
  • Multifocal lesions (23%) involving medial temporal lobe, midbrain, hypothalamus, and thalamus 1
  • Periventricular leukopathy (6%)
  • Diffuse cortical atrophy (18%)
  • Pachymeningitis (12%)
  • Normal findings despite neurological symptoms (17%) 1

Laboratory Testing

• CSF analysis:

  • Normal cytology in 62% of cases 1
  • T. whipplei PCR positive in 92% of tested CSF samples 1
  • PCR is more sensitive than other techniques 2

• Brain biopsy (when accessible):

  • PAS-positive macrophages containing T. whipplei 1

Treatment Considerations

Antibiotic Regimens

• Initial treatment with parenteral antibiotics that cross the blood-brain barrier is essential 2
• Common regimens include:
  • Doxycycline (200 mg/24h) plus hydroxychloroquine (200-600 mg/24h) orally for ≥18 months 4
  • Alternative: Ceftriaxone (2g/24h IV) for 2-4 weeks followed by oral therapy 4

Prognosis

• With appropriate treatment, clinical outcomes are favorable in approximately 78% of patients 1
• Mild to moderate neurological sequelae may persist in about 50% of treated patients 1
• Without treatment, CNS Whipple's disease is typically fatal 3
• Early recognition and treatment are critical to prevent irreversible neurological damage 3

Clinical Pearls and Pitfalls

• Key Diagnostic Pearl: Oculomasticatory myorhythmia is considered pathognomonic for CNS Whipple's disease 3

• Important Pitfall: CNS Whipple's disease can mimic almost any neurological condition, leading to misdiagnosis as neurodegenerative disorders, stroke, or tumors 5

• Treatment Consideration: CNS involvement may occur during or after trimethoprim-sulfamethoxazole treatment, suggesting this regimen may be insufficient for CNS disease 1

• Monitoring: All patients with Whipple's disease should be treated and monitored as if they have CNS disease, even if neurologically asymptomatic 2

• Relapse Risk: The CNS is the most common site of disease relapse, and neurological relapses tend to be more resistant to treatment than systemic relapses 3