How can a patient with a history of cancer treatment, specifically chemotherapy for brain tumors, develop neuropathy without having diabetes?

Neuropathy Without Diabetes: Chemotherapy-Induced Peripheral Neuropathy

In a patient with a history of chemotherapy for brain tumors, the neuropathy is almost certainly chemotherapy-induced peripheral neuropathy (CIPN), which is one of the most common and underestimated long-term side effects of cancer treatment. 1

Chemotherapy as a Primary Cause of Neuropathy

Chemotherapy-induced neuropathy is now one of the most common side effects of cancer treatment, surpassing bone marrow suppression and kidney dysfunction in frequency. 2 The specific chemotherapy agents used for brain tumors determine the likelihood and pattern of neuropathy:

High-Risk Neurotoxic Agents

• Platinum-based drugs (cisplatin, carboplatin, oxaliplatin) cause dose-dependent peripheral sensory neuropathy that can persist lifelong in 15-40% of patients 1
• Taxanes (paclitaxel, docetaxel) produce predominantly sensory neuropathy affecting lower limbs more prominently, with symptoms typically improving months after treatment completion 3, 2
• Vinca alkaloids (vincristine) cause motor neuropathy in approximately 10% of patients, ranging from mild distal weakness to severe motor neurotoxicity 4, 2

Clinical Pattern Recognition

The neuropathy presents as:

• Sensory symptoms in a "glove and stocking" distribution starting distally in fingers and toes, with numbness, tingling, burning, and pain 3
• Dose-dependent severity based on cumulative chemotherapy exposure 1
• "Coasting phenomenon" where oxaliplatin-induced neuropathy paradoxically worsens for 2-3 months after treatment completion before improving 3

Other Non-Diabetic Causes to Consider

While chemotherapy is the most likely culprit in this patient, 10-50% of patients may have additional potential causes of neuropathy that should be systematically excluded: 5

Nutritional Deficiencies

• Vitamin B12 deficiency causes both symptomatic and asymptomatic small fiber loss similar to diabetes 4
• Vitamin E, thiamine, nicotinamide, and folate deficiencies particularly in patients with malabsorption 4
• Copper deficiency should be considered 4

Medication-Related Causes

• Neurotoxic medications beyond chemotherapy (metronidazole, anti-TNF agents) 4
• Alcohol abuse is a common neurotoxin that must be assessed 4

Disease-Related Causes

• Hypothyroidism 1
• Renal disease and chronic kidney disease 1, 4
• Monoclonal gammopathies and plasma cell dyscrasias (POEMS syndrome, amyloidosis) 4
• Chronic inflammatory demyelinating neuropathy (CIDP) 1, 5
• Hepatitis C infection with cryoglobulins 4
• HIV infection 1, 4

Hereditary Causes

• Charcot-Marie-Tooth disease should be ruled out, especially if there is family history or severe motor involvement with distinctive deformities (hollow foot, stork legs) 4
• Family history of hereditary neuropathies predisposes to chemotherapy-induced neuropathy 4, 3

Diagnostic Approach

The diagnosis of CIPN is generally made through clinical history, but other causes must be systematically excluded: 3

Essential Workup

• Detailed medication history including all chemotherapy agents, cumulative doses, and timing 1
• Thyroid function tests (TSH) 1
• Vitamin B12 level 1, 4
• Renal function (creatinine, eGFR) 1
• Serum protein electrophoresis to screen for monoclonal gammopathies 4
• HIV testing in at-risk populations 1, 4
• Alcohol use assessment 4

Neurological Examination

• Small-fiber function: pinprick and temperature sensation 1
• Large-fiber function: vibration perception using 128-Hz tuning fork and 10-g monofilament testing 1
• Assessment for motor weakness and gait abnormalities 4

When to Consider Electrophysiology

Electrophysiological testing or referral to a neurologist is rarely needed except when clinical features are atypical or the diagnosis is unclear. 1 However, if known neurotoxic chemotherapy was used, early electrophysiological evaluation helps both patients and physicians prepare for possible neurotoxic effects. 2

Management Considerations

For Established CIPN

Duloxetine is the only medication with adequate evidence for treating painful CIPN, starting at 20 mg daily for one week, then increasing to 40 mg daily. 1, 3

Supportive Care Measures

• Physical activity and physiotherapy to improve coordination and sensorimotor function 1
• Referral to podiatrists for footwear education 1
• Acupuncture may be considered in selected patients, though evidence is limited 1
• Vitamin B supplementation can be discussed, though evidence for efficacy is limited 1

Medications with Limited Evidence

• Gabapentin or pregabalin have limited evidence for CIPN specifically, though they are effective for other neuropathic pain conditions 1
• Tricyclic antidepressants (nortriptyline, desipramine) are reasonable to try despite limited CIPN-specific evidence 1

Critical Pitfalls to Avoid

• Do not assume all neuropathy in cancer patients is chemotherapy-related without excluding other treatable causes like B12 deficiency, hypothyroidism, or CIDP 1, 5
• Up to 50% of peripheral neuropathy may be asymptomatic, so absence of symptoms does not rule out significant nerve damage 1, 4
• Do not use acetyl-L-carnitine, as it may worsen neuropathy 3
• Recognize that CIPN can persist lifelong in 15-40% of patients after taxane chemotherapy, significantly impacting quality of life 1
• Be aware of the "coasting phenomenon" where neuropathy worsens for 2-3 months after stopping oxaliplatin before improving 3