Disorders of the GI system, including luminal diseases of the stomach and bowel, as well as pancreatic and hepatic disorders, can lead to neurologic complications affecting the central nervous system (CNS) and the peripheral nervous system, both of which can present with lower extremity findings.

IBD is a chronic inflammatory GI disease comprised of Crohn disease (CD) and ulcerative colitis (UC), which can affect the entire GI tract, particularly the small and large intestines. The course for each individual patient can be highly variable, and many with the disease have relapsing and remitting disease. The underlying driving force of the disease is not entirely understood, but one’s environment, genetics, and immune system (T₁ helper cells in CD and T₂ helper cells in UC) all play an important role. Most patients present between the ages of 15 and 40. CD may present with abdominal pain, diarrhea, GI tract obstruction, perianal fistulas or abscesses, and weight loss. UC often presents with bloody diarrhea, urgency, tenesmus, and pain with defecation.¹ Aside from GI-specific manifestations, IBD can be associated with extraintestinal manifestations that can affect multiple other organ systems including the nervous, dermatologic, vascular, orthopedic, and rheumatologic systems.² Neurologic involvement in IBD is one aspect of extraintestinal manifestation that can be seen in patients with IBD. Peripheral neuropathy is a common neurologic manifestation, and may be related to medications including metronidazole and anti-tumor necrosis factor (TNF) agents, vitamin deficiencies, and immune-mediated changes.³

The reported incidence of neurologic manifestations in patients with IBD is thought to be approximately 3%,⁴ of which the prevalence of peripheral neuropathy in particular has been reported to be as high as 13.4%,⁵ with relatively comparable incidence in patients with UC and CD. These peripheral neuropathies may be sensory, motor, mixed, or autonomic. They may be acute or chronic, axonal or demyelinating, and may have various distributions.⁶ Patients may also experience primary muscle involvement that may be confused with neuropathies; these can include inflammatory myopathies, dermatomyositis, polymyositis, rimmed vacuole myopathy, and granulomatous myositis.³

Peripheral neuropathies in IBD are not typically related to disease activity, and do not respond to treatment of the underlying IBD.³ The underlying pathology of peripheral neuropathies may be immune-mediated, secondary manifestations of vitamin deficiencies (such as low vitamin B₁₂ or vitamin B6), or medication side effects (from metronidazole or anti-TNF agents). Patients may experience malabsorption secondary to surgical changes (e.g., vitamin B12 deficiency after ileal resections) or disease activity (ileal inflammation leading to decreased vitamin B12 deficiency).⁷ Anti-TNF agents have been associated with peripheral and central demyelination, both new cases and aggravation of old cases. Natalizumab, which is an anti-integrin also approved for use in patients with IBD, has been associated with progressive multifocal leukoencephalopathy (PML) in patients with John Cunningham (JC) virus.⁸

Another notable neurologic condition associated with IBD is multiple sclerosis (MS). MS has been more frequently associated with UC than CD. The prevalence of MS is increased in patients with concomitant IBD.⁹ Furthermore, patients with IBD are also more likely to have asymptomatic white matter lesions, although the clinical significance of these findings remains unclear.¹⁰ The pathophysiology of this relationship is unclear, but likely is related to the underlying inflammatory and immunologic pathology that drives both
MS and IBD. Notably, anti-TNF agents are contraindicated in patients with MS, as they have been associated with new onset of demyelination and aggravation of preexisting disease.¹¹

There have also been rare reports of fistulization from the rectum to the epidural and subdural spaces, leading to abscess formation and subsequent nerve compression with development of lower extremity weakness, pain, and other neurologic complications.¹²,¹³ Although rare and uncommon, sudden onset of focal neurologic findings in the lower extremities should trigger an extensive workup, examining for peripheral neurologic conditions as well as brain and spinal cord pathology.

Hepatitis C virus (HCV) infection is one of the leading causes of cirrhosis, with significant morbidity and mortality globally.¹⁴ It is often asymptomatic initially, but can become a chronic liver infection in over 80% of those infected with the virus.¹⁵ HCV can independently be associated with peripheral neuropathy.¹⁶ It is thought that HCV can trigger an immunologic response including production of antiganglioside antibodies (1 and 2), which may be related to the development of neuropathy.¹⁷ Individuals infected with hepatitis C may also develop cryoglobulinemia, which is characterized by significant cryoglobulins (proteins that become insoluble complexes at cold temperatures) in the blood. Cryoglobulinemia can lead to deposition of immune complexes in small and medium-sized vessels with vascular inflammation, as well as mononeuropathy or mononeuropathy multiplex in 17% to 60% of patients.³ Other hepatitides may also be associated with neurologic manifestations. Hepatitis A virus (HAV) is an acute, often self-limited hepatitis characterized by jaundice, abdominal pain, fever, nausea, vomiting, and diarrhea. HAV infection can rarely precede Guillain-Barré syndrome (which most commonly presents with ascending paralysis of the lower extremities).¹⁸ Hepatitis B virus (HBV) is responsible for both acute and chronic hepatitis infections and may present with jaundice, abdominal pain, nausea, and vomiting. HBV infection can rarely be associated with Guillain-Barré syndrome,¹⁹ as well as mononeuropathy multiplex and acute symmetrical vasculitic polyneuropathy (which presents as nonpalpable purpura, and acute-onset distal symmetric sensorimotor polyneuropathy).²⁰,²¹

In terms of the CNS, multiple GI disorders (including IBD, HCV infection, and cirrhosis) have been associated with increased risk of stroke. This may present with focal neurologic deficits (isolated motor or sensory, or mixed) in the lower extremities. For example, patients may present with unilateral lower extremity weakness, numbness, or gait instability. Clinicians should have a low threshold to rule out a cerebral vascular accident in individuals who suffer from one of the aforementioned GI disorders and who present with focal neurologic findings. Cirrhotics often have an imbalance of prothrombotic and antithrombotic factors that are synthesized by the liver, which can make these individuals prone to hemorrhage or increased clot formation.²² In those with IBD, the underlying mechanism driving an increased risk of stroke may be secondary to a systemic inflammatory state, leading to increased levels of factor V and VIII, fibrinogen, decreased levels of protein S and antithrombin, leading to a prothrombotic state. Other possible theories that have been proposed to explain why patients with IBD have an increased risk of clot formation include platelet dysfunction, increased von Willebrand factor, and increased levels of homocysteine.³ Those with IBD have an increased risk of both arterial and venous thrombi.⁶,²³ Autopsy records estimate a prevalence as high as 30% for those with UC, and the incidence of thrombotic complications ranges from 0.5% to approximately 7% per year.²⁴ They are not related to the duration or the severity of IBD, but cerebrovascular events are more frequent during bouts of inflammation. There have also been case reports of ischemic strokes thought to be complications of anti-TNFα therapy. There have also been reports of thrombosis of the dural sinus and cerebral veins, and this, perhaps, is more common in the pediatric population.²⁵,²⁶

Acute liver failure (ALF, also known as fulminant hepatic failure) and cirrhosis may both be associated with encephalopathy, which can involve lower extremity findings. Encephalopathy seen in ALF is secondary to astrocyte swelling and progression to cerebral edema, with or without herniation.²⁷ In cirrhosis, encephalopathy is often thought to be driven by accumulation of toxins not cleared by the liver, which can be triggered by infections, GI bleeding, and constipation; in the case of cirrhosis, encephalopathy is known as portosystemic encephalopathy (PSE) or hepatic encephalopathy (HE).²⁸ Encephalopathy secondary to ALF or cirrhosis can manifest with subtle findings such as myoclonus or stark changes such as frank coma with posturing.²⁹ Although it would be rare to see isolated lower extremity manifestations in these conditions, one should still be aware of even subtle changes in the lower extremities as these help one recognize and grade the degree of HE. With resolution of liver disease, one would expect resolution of the neurologic manifestations. Although rare, after several episodes of PSE, cirrhotic patients can develop hepatic myelopathy, or a complex movement disorder known as acquired hepatocerebral degeneration. Hepatic myelopathy is caused by demyelination of the lateral corticospinal tracts and eventual axonal loss. It is characterized by a subacute progressive bilateral lower extremity weakness and spasticity, with minimal to no sensory abnormalities.³⁰,³¹ Acquired hepatocerebral degeneration presents with parkinsonism of predominantly lower body involvement, postural instability, and cranial dyskinesia; there may also be tremors, limb dystonia, and chorea.³²,³³ In making these diagnoses, one must be careful to rule out metabolic etiologies (including hypoglycemia, hyponatremia), thiamine deficiency, as well as alcohol or recreational drug use. Patients should also undergo a CT of the head/brain to evaluate for evidence of intracranial bleed, and an MRI to rule out an ischemic event. An MRI can also be helpful in making the diagnosis, as it may reveal T1 bilateral high-signal abnormalities in the pallidum and substantia nigra, related to deposition of manganese.³⁴