Hereditary Spastic Paraplegia

Hereditary spastic paraplegia is a group of inherited neurodegenerative disorders with progressive lower limb spasticity and weakness from degeneration of corticospinal tract axons. Over 80 genetic loci are known.

Prevalence is about 2 to 6 in 100,000. Inheritance may be autosomal dominant, autosomal recessive, X-linked or mitochondrial.

Classification. Pure forms have spastic paraparesis with mild sensory loss and bladder urgency. Complicated forms add neuropathy, cognitive impairment, epilepsy, ataxia, optic atrophy, deafness or a thin corpus callosum.

Genetics. The commonest causes are SPAST (SPG4, about 40% of dominant cases), ATL1 (SPG3A, early onset), REEP1 and KIF5A (dominant), and SPG11, SPG7 and SPG15 (recessive). SPG11 gives complicated disease with a thin corpus callosum.

Pathophysiology. Length dependent axonal degeneration of corticospinal tracts and dorsal columns arises from defects in axonal transport, endoplasmic reticulum shaping, lipid metabolism and mitochondrial function.

Presentation is insidious stiffness and weakness of the legs with a scissoring or toe walking gait, hyperreflexia, extensor plantar responses, reduced vibration sense and urinary urgency. Arms are mildly affected. Onset ranges from childhood to late adulthood, and progression is slow. Pes cavus and scoliosis may appear. Complicated forms add features of the associated syndrome.

Diagnosis needs a compatible progressive course, family history and exclusion of treatable causes. MRI of brain and whole spine is needed. Check vitamin B12, folate, copper, very long chain fatty acids, HTLV-1 serology, HIV and syphilis serology, thyroid function and lipid profile. A short course of levodopa excludes dopa responsive dystonia in children. Confirm with a multigene panel or exome sequencing.

Differential diagnosis.

• Compressive and other structural myelopathy, multiple sclerosis and primary lateral sclerosis.
• Vitamin B12 and copper deficiency, adrenomyeloneuropathy, HTLV-1 myelopathy and spinal dural arteriovenous fistula.
• Cerebral palsy in children, and dopa responsive dystonia.

There is no disease modifying treatment. Care is symptomatic and multidisciplinary.

Spasticity.

• Baclofen 5 mg orally three times daily, increased every 3 to 7 days to a usual range of 30 to 80 mg daily in three or four divided doses (maximum 100 mg daily). Start at 5 mg once or twice daily and increase slowly in older adults and in renal impairment, and avoid in eGFR under 30 mL/min unless closely supervised. Do not stop abruptly (seizures, hallucinations, rebound spasticity).
• Tizanidine 2 mg at night, increased gradually to 4 to 8 mg three times daily (maximum 36 mg daily). Check liver tests at baseline and monthly for 4 months. Avoid with ciprofloxacin or fluvoxamine.
• Botulinum toxin injections to hip adductors, hamstrings and calf muscles every 3 to 4 months, adjusting to the product label.
• Intrathecal baclofen by pump for severe spasticity not controlled by oral drugs.

Bladder. Oxybutynin 2.5 to 5 mg orally two or three times daily, or mirabegron 25 to 50 mg daily, and check post-void residual volume.

Rehabilitation. Regular stretching, strengthening, treadmill exercise, ankle foot orthoses and gait aids, orthopaedic surgery for fixed contractures.

Other. Treat pain, fatigue, depression and osteoporosis, and offer genetic counselling.

Monitoring. Gait speed, spasticity scale and liver tests (tizanidine) every 6 to 12 months.

Referral and escalation. Refer to neurology and clinical genetics. Refer urgently for rapid progression, new sensory level or sphincter loss, which suggests another cause.