What is the differential diagnosis for a patient with Moyamoya disease, pancreatic cancer, and hepatic cancer presenting with bilateral (b/l) weakness, burning sensation in the legs, and dizziness upon changing positions?

Differential Diagnosis for Patient with Moyamoya, Pancreatic Cancer, and Hepatic Cancer Presenting with Bilateral Weakness, Burning Legs, and Orthostatic Dizziness

The most likely diagnoses are paraneoplastic peripheral neuropathy from the pancreatic or hepatic malignancies, chemotherapy-induced peripheral neuropathy if receiving treatment, or cerebral hypoperfusion from moyamoya disease causing bilateral weakness, with orthostatic hypotension from autonomic dysfunction or volume depletion as a contributing factor.

Primary Neurological Considerations from Moyamoya Disease

Cerebral Hypoperfusion Syndrome

• Bilateral weakness in moyamoya can result from chronic cerebral hypoperfusion affecting watershed zones bilaterally, particularly the frontal subcortical regions which control motor function 1.
• Neurocognitive impairment from chronic cerebral hypoperfusion is a recognized manifestation of moyamoya disease, and motor symptoms can accompany this 1.
• Hypoperfusion of frontal cortical and subcortical regions can cause motor dysfunction through ischemic imbalance in the cortical-subcortical-ganglionic-thalamic-cortical circuitry 2.

Progressive Ischemic Events

• In symptomatic moyamoya patients managed conservatively, the 5-year risk of recurrent ischemic events is 65% for unilateral disease and 82% for bilateral involvement 1.
• Bilateral watershed infarcts involving frontal subcortical regions could explain bilateral weakness 2.
• The 2-week duration suggests either progressive ischemia or a subacute stroke event rather than acute presentation 1.

Movement Disorders and Atypical Presentations

• Moyamoya can present with movement disorders including involuntary limb movements, though this is rare 2.
• Secondary movement disorders are recognized neurological symptoms of moyamoya 1.

Oncologic and Paraneoplastic Etiologies

Paraneoplastic Peripheral Neuropathy

• Pancreatic cancer commonly causes paraneoplastic syndromes, and peripheral neuropathy with burning sensations is a classic presentation 1, 3.
• Weight loss is an important feature of pancreatic cancer and would be expected in this patient 1.
• The burning sensation in legs strongly suggests peripheral neuropathy rather than central nervous system pathology 1.

Direct Metastatic Involvement

• Pancreatic cancer has a >95% mortality rate with most patients having metastatic disease at diagnosis 1.
• Hepatic metastases or primary hepatic cancer could cause metabolic derangements contributing to weakness 1, 3.
• Spinal or leptomeningeal metastases should be considered with bilateral lower extremity symptoms 1.

Metabolic and Nutritional Complications

• Pancreatic cancer can cause malabsorption and nutritional deficiencies leading to peripheral neuropathy 1.
• Recent-onset diabetes occurs in up to 10% of pancreatic cancer patients and could contribute to diabetic neuropathy, though the 2-week timeframe is short for this 1, 3.

Autonomic and Cardiovascular Causes

Orthostatic Hypotension

• The orthostatic dizziness suggests autonomic dysfunction, which can occur from paraneoplastic autonomic neuropathy or volume depletion from cancer cachexia 1.
• Pancreatic neuroendocrine tumors can cause VIPoma syndrome with profuse watery diarrhea and marked hypokalemia leading to weakness and orthostatic symptoms, though this represents <10% of pancreatic tumors 1.

Carcinoid Syndrome (if Neuroendocrine Component)

• If the pancreatic cancer has neuroendocrine features, carcinoid syndrome could cause flushing, diarrhea, and weakness, though burning leg sensations are not typical 1.

Critical Diagnostic Approach

Immediate Neuroimaging

• MRI with diffusion-weighted imaging to detect acute/subacute infarcts in moyamoya, as acute infarcts are best seen with this modality 1.
• MRA to assess current status of moyamoya vasculopathy and progression 1.
• Evaluate for leptomeningeal or spinal metastases that could cause bilateral symptoms 1.

Hemodynamic Assessment

• Consider cerebral perfusion imaging (MRI with arterial spin labeling, CT perfusion, or SPECT) to identify cerebral hemodynamic impairment, which predicts stroke risk in moyamoya 1.
• Orthostatic vital signs to document orthostatic hypotension 1.

Peripheral Neuropathy Workup

• Electromyography and nerve conduction studies to confirm peripheral neuropathy and characterize the pattern 1.
• Assess for chemotherapy exposure if patient is receiving treatment 1.
• Check B12, thiamine, and other nutritional markers given malignancy and potential malabsorption 1.

Metabolic and Oncologic Assessment

• Comprehensive metabolic panel including calcium, glucose, and liver function tests 1, 3.
• Assess for hypercalcemia from malignancy, which can cause weakness and altered mental status 1.
• Evaluate for progression of pancreatic or hepatic cancer with CT imaging 1, 3.

Key Clinical Pitfalls to Avoid

Don't Attribute Everything to Moyamoya

• While moyamoya can cause bilateral symptoms, the burning sensation in legs is more consistent with peripheral neuropathy than central ischemia 1, 2.
• Moyamoya typically presents with transient ischemic attacks, stroke, or hemorrhage rather than subacute progressive bilateral weakness 4, 5.

Consider Rapid Moyamoya Progression

• Moyamoya can progress from unilateral to bilateral disease rapidly, documented in as little as 6 weeks, and progression occurs in approximately 20% of patients 1, 5.
• Progressive disease is associated with ischemic or hemorrhagic symptoms in >50% of patients with progression 1.

Don't Miss Treatable Causes

• Paraneoplastic syndromes may respond to treatment of the underlying malignancy 1.
• If moyamoya is causing progressive ischemia, surgical revascularization should be considered urgently, as conservative management has poor outcomes 1.

Screen for Moyamoya Syndrome vs. Disease

• Given the multiple malignancies, determine if this represents moyamoya disease (idiopathic) or moyamoya syndrome (secondary to another condition) 1, 6.
• Brain tumors and head irradiation are associated with moyamoya syndrome 1, 6.
• This distinction matters because moyamoya syndrome may require treatment of the underlying condition 6.

Most Likely Unified Diagnosis

The clinical picture most likely represents a combination of paraneoplastic peripheral neuropathy from advanced pancreatic/hepatic malignancy (explaining the burning legs and weakness) with concurrent orthostatic hypotension from autonomic dysfunction or volume depletion (explaining the positional dizziness). The moyamoya disease may be contributing through chronic cerebral hypoperfusion, but the burning quality of leg symptoms points more toward peripheral nerve involvement 1, 2.