Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer disease, and Parkinson disease (PD), and the central nervous system demyelinating disorder, multiple sclerosis (MS), are becoming more prevalent with lengthening life spans.¹ Evaluation and treatment of motor and cognitive decline is necessary to help preserve patient’s quality of life. Although these diseases do not have a cure, symptomatic management can improve patient quality of life and survival. This chapter will focus on pain, particularly brain-related causes of foot and ankle pain in the above neurodegenerative disorders along with cerebral palsy (CP) and immune neuropathies.

Pain has been an often underrecognized and undertreated symptom; cognitive impairment may further complicate the assessment. Pain is often either neuropathic or nociceptive in origin.¹

Neuropathic pain, whether it be central or peripheral, results from lesions in the central or peripheral somatosensory system.² It is pain that originates from nervous system pathology.³

With nociceptive pain, patients have a normally functioning somatosensory nervous system but there is damage to tissue unrelated to the nervous system, which causes activation of the nociceptors.² For example, patients with reduced mobility or motor impairment with hypertonia can have secondary osteoarthritic problems resulting in local inflammation and pain.¹

In the patient evaluation of leg pain, motor neuron disease, particularly ALS, should be considered. It is the most common neurodegenerative disorder involving the motor system. ALS is a progressive neurodegenerative disease, causing weakness in the extremities, progressing to development of bulbar symptoms such as dysarthria, dyspnea, and dysphagia.² Pseudobulbar affect is also noted. Outcome is fatal, usually within 2 to 4 years from disease onset.² Pain is primarily associated with immobility.⁴ Spasticity and cramping are common in the extremities and are associated with varying degrees of pain. There is degeneration of primary motor neurons in the cortex, spinal cord, and brain stem. This causes “amyotrophy,” leading to muscle paralysis due to loss of innervating neurons.¹ “Lateral sclerosis” refers to upper motor neuron axonal loss, hardening of corticospinal tracts, and gliosis.

Degeneration of motor neurons occurs primarily; however, the sensory system can also be involved.

Spinocerebellar involvement can cause balance dysfunction noted by patients early in the disease.

Until about 10 years ago, pain was a neglected symptom in ALS. Since ALS was and is considered a purely motor disease, pain was often not asked about.² It is, however, very important to identify and assess pain particularly to help improve patient outcomes and quality of life. Pain can increase with the disease duration and decreased functional status. The cause of pain, whether primarily neuropathic, related to the impairment of somatosensory pathways, or nociceptive, related to the effects of tissue damage, needs to be distinguished in
order to determine the best approach to treatment. Neuropathic pain is not mechanical. It has features of nerve irritation. The mechanism of neuropathic pain includes central or peripheral sensitization, atrophy of cortical areas, or reduced descending inhibition. Spasticity and cramps are common primary causes of pain in patients with ALS. Cramps originate from instability of motor units at the level of distal motor nerves and are usually associated with muscle denervation. Secondary nociceptive causes of ALS pain can develop as the disease progresses. Atrophy and weakness of muscles and prolonged immobility cause degenerative changes in connective tissue, bones, and joints, leading to musculoskeletal pain.¹ Joint contractures are common. Pain is often associated with these muscle contractures, decreased joint mobility, muscle cramps, skin pressure, and spasticity. Pain may also occur as a manifestation of a small fiber neuropathy found in skin biopsies in 79% of patients with ALS in a study done by Weis et al.⁵ Reflex sympathetic dystrophy in rare cases has also been seen in ALS.⁶

A case control study done on neuromuscular diseases found pain present in 73% of patient population with ALS.¹ Areas of pain involvement were noted in the back, shoulder, neck, buttock, hip, feet, arms, and hands.¹ In the study done by Hanisch et al, of the 46 patients with ALS studied, 63% reported of having cramps.⁴ Pain seems to originate from motor unit instability and muscle denervation.³ Sites of cramps reported were calf (57%), hands and fingers (43%), and feet and toes (30%).⁴ Cramps occurred most frequently at night and less frequently with daytime movement. Cramping in ALS in the distal small muscles of the toes/feet and in fingers/hands is usually short lasting, is movement induced, and can interfere with functional activities. The involvement of feet intrinsic muscles rather than calves seems to be typical of ALS and helps in differentiating it from benign cramps.³,⁷

ALS is primarily a clinical diagnosis, and common symptoms and signs include difficulty walking; tripping; falling; slurred speech; drooling; muscle cramps; twitches in the arms, legs, shoulders, and tongue; dropping things; weakness in the arms and legs; and muscle atrophy.

Performing a thorough musculoskeletal examination is important.

Electrodiagnostic testing, primarily EMG, and nerve conduction studies help to rule out myopathy or motor neuropathies with demyelination or conduction block. Fasciculations are seen in the upper and lower extremities and tongue.

Magnetic resonance imaging (MRI) of the brain and spine is helpful in ruling out other neurologic conditions.

The most commonly occurring immune-mediated neuropathy is Guillain-Barré syndrome. This is acute inflammatory demyelinating polyradiculoneuropathy. Typical presentation is that of acute paralysis with areflexia. It can be classified into several different types:

With Guillain-Barré syndrome, as opposed to chronic inflammatory demyelinating polyneuropathy (CIDP), the time to reach maximum clinical deficit is 4 weeks rather than 8 weeks. Approximately 70% of Guillain-Barré cases are preceded by an infectious illness, often gastrointestinal or respiratory, vaccination, or surgery by 3 to 4 weeks before the onset of clinical symptoms.⁹ Annual incidence is reported to be 1.2 to 2.3 per 100,000. The incidence increases with age, and men are affected slightly more than women.¹⁰