Neuroprotection (Acute Phase)

Granulocyte-Colony Stimulating Factor

Granulocyte-colony stimulating factor (G-CSF), a pharmaceutical agent that is normally used to treat neutropenia, has recently been investigated for its potential role in the treatment of acute SCI. The main function of G-CSF is apoptosis inhibition and stimulation of neuron differentiation from new bone marrow-derived cells (Schneider et al. 2005). It also suppresses the expression of inflammation-causing cytokines and protects the myelin sheath surrounding the axons of neurons (Takahashi et al. 2012). Recent studies in animal models have found G-CSF to enhance neurological recovery (Koda et al. 2007; Nishio et al. 2007), and its potential use in other neurological disorders, such as stroke, is under investigation (Schneider et al. 2005).

Author Year

Country

Research Design

Sample Size

 Methods Outcomes
Kamiya et al. 2014

Japan

Cohort

N=28

 Population: Age range=18-35 yr; Gender: male=75%, female=25%; Level of injury: C3-C7; Severity of injury: complete=7%, incomplete=93%, AIS A-D.

Treatment: In this phase I/IIa clinical trial, all patients received 10 µg/kg/day granulocyte colony-stimulating factor (G-CSF) intravenously for 5 days beginning within 48 hr of injury. Historical records of patients administered methylprednisolone sodium succinate (MPSS) according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines served as a control.

Outcome Measures: The following after 3 months: ASIA motor function, neurological recovery based on AIS, adverse event outcomes.

Chronicity: Treatment was initiated within 48 hr after injury.
  1. ASIA motor score: Overall, patients who received G-CSF recovered significantly more motor function than patients in the historical control group (p<0.01). This significant difference remained even after removing patients with complete injuries.
  2. AIS: Overall, there was no difference in neurological recovery of one step of the AIS between patients who received G-CSF and the historical control group (p>0.05); however, significantly more patients who received G-CSF experienced an improvement of 2 steps than those in the historical control group (p<0.05). This significant difference remained even after removing patients with complete injuries.
  3. Patients in the historical control group experienced significantly more incidences of pneumonia than patients who received G-CSF (p<0.05).
Takahashi et al. 2012

Japan

Prospective Controlled Trial

N=16

 Population: Age range=18-75 yr; Gender: male=81%, female=19%; Level of injury: cervical-thoracic; Severity of injury: complete=6%, incomplete=94%.

Treatment: In this open label phase I/IIa clinical trial, patients received either low dose granulocyte-colony stimulating factor (G-CSF) (5 µg/kg/day) or moderate dose G-CSF (10 µg/kg/day). Treatment was administered intravenously for five days beginning within 48 hr of injury. Historical records of patients administered methylprednisolone sodium succinate (MPSS) according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines served as a control.

Outcome Measures: The following daily during the first week, 1 month after injury, and 3 months after injury: body temperature, blood data, ASIA motor function, ASIA sensory function (pinprick and light touch).

The following after 3 months:

Neurological recovery based on the ASIA scale.

Chronicity: Individuals were treated within 6.4-48 hr of sustaining injury.
  1. There were no significant differences in body temperature in either patients who received low dose G-CSF or those who received high dose G-CSF during the first week of hospital stay, 1 month after injury, or 3 months after injury compared to baseline (p>0.05).
  2. During the first 5 days after administration, there was a significant elevation of white blood cells in both low dose and moderate dose patients compared to their baseline levels (p<0.01) that returned to normal after the G-CSF administration ended. There was a significant elevation of C-reactive protein after 1 day in patients who received high dose G-CSF (p<0.05) but these levels returned to normal the day after.
  3. Patients who received moderate dose G-CSF experienced significantly higher motor function score after 1 day (p<0.01), pinprick score after 2 days (p<0.05), and light touch score after 2 days (p<0.05) that remained significant at every follow up time point.
  4. Patients who received low dose G-CSF and patients in the historical control group did not experience significant improvements in motor or sensory function (p>0.05).
  5. There were no significant differences in neurological recovery of 1 grade based on the AIS among the 3 groups after 3 months (p>0.05).
  6. Patients who received either low or moderate dose G-CSF did not experience significant adverse event outcomes compared to patients in the historical control (p>0.05). There were significantly higher rates of pneumonia in the MPSS historical control group compared to the G-CSF groups (p>.05).

Discussion

Two clinical trials (Takahashi et al. 2012; Kamiya et al. 2014) have been recently conducted to examine whether G-CSF improves neurological recovery in acute SCI. It is promising to see initial improvements in neurological function compared to baseline measurements, especially in those experiencing incomplete injuries (Kamiya et al. 2014). However, despite positive findings, it is important to note that the sample sizes were small and the protocols lacked blinding and randomization. While the authors noted significantly fewer episodes of pneumonia using G-CSF instead of MP, there is still a concern with other side effects such as elevated levels of white blood cells. It is known that white blood cell counts in the levels of 50 000 cells/mm3 can cause splenic rupture, and significantly higher white blood cell counts were observed in both groups receiving treatment, with one patient experiencing counts in this dangerous level (Kamiya et al. 2014). Additional RCTs examining the role of G-CSF in acute SCI are recommended.

Conclusion

There is level 2 evidence (from one cohort study and one prospective controlled trial: Kamiya et al. 2014; Takahashi et al. 2012) that a moderate dose (10 µg/kg/day) of granulocyte-colony stimulating factor may be effective in promoting motor and sensory recovery in acute SCI individuals.

Granulocyte-colony stimulating factor may be effective for neurological recovery during the acute phase post-SCI.

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